Modification of cupredoxin derived peptides and methods of use thereof

ABSTRACT

The present invention provides modified cupredoxin derived peptides with pharmacologic activity that have improved pharmacokinetic properties, and methods to use them to treat mammals suffering from various conditions related to the pharmacologic activities. Modifications of the cupredoxin derived peptides include amino acid sequence variants and structural derivations that increase the plasma half-life of the peptide, increase the specific activity of the pharmacologic activity, decrease immunogenicity, and decrease the biotransformation of the peptides. The modified cupredoxin derived peptides can be used in methods to treat mammals for cancer, conditions related to inappropriate angiogenesis, viral and bacterial infections, and specifically HIV and malaria, conditions related to ephrin signaling, and to deliver cargo compounds, including diagnostic compounds, to cancer cell

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. §§119 and 120 to, andis a continuation of U.S. patent application Ser. No. 12/389,120, filedon Feb. 19, 2009, which is a continuation in part of U.S. patentapplication Ser. No. 12/314,703, filed on Dec. 15, 2008, now abandoned,which claims priority to U.S. Patent Application Ser. No. 61/013,709,filed on Dec. 14, 2007; and is a continuation in part of U.S. patentapplication Ser. No. 11/853,497, filed Sep. 11, 2007, which claimspriority to Provisional U.S. Application Ser. No. 60/843,388, filed Sep.11, 2006; and is a continuation in part of U.S. patent application Ser.No. 11/244,105, filed Oct. 6, 2005, issued on Apr. 6, 2010 as U.S. Pat.No. 7,691,383, which claims priority to U.S. Provisional PatentApplication No. 60/616,782, filed Oct. 7, 2004, U.S. Provisional PatentApplication No. 60/680,500, filed May 13, 2005, and U.S. ProvisionalPatent Application No. 60/700,297, filed Jul. 19, 2005. The entirecontent of those applications are fully incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to modified cupredoxin derived peptideswith pharmacologic activity that have improved pharmacokineticproperties, and methods to use them to treat mammals suffering fromvarious conditions related to the pharmacologic activities.Modifications of the cupredoxin derived peptides include amino acidsequence variants and structural derivations that may increase theplasma half-life of the peptide, increase the specific activity of thepharmacologic activity, decrease immunogenicity, and/or decrease thebiotransformation of the peptides. The modified cupredoxin derivedpeptides can be used in methods to treat mammals for cancer, conditionsrelated to inappropriate angiogenesis, viral and bacterial infections,and specifically HIV and malaria, conditions related to ephrin signalingand deliver cargo compounds, including diagnostic compounds, to cancercells.

BACKGROUND

The cupredoxin azurin from Pseudomonas aeruginosa is a promising newtherapeutic and diagnostic molecule. Two redox proteins elaborated by P.aeruginosa, the cupredoxin azurin and cytochrome c_(SSI) (Cyt c_(SSI))both enter J774 cells and show significant cytotoxic activity towardsthe human cancer cells as compared to normal cells. Zaborina et al.,Microbiology 146: 2521-2530(2000). Azurin can also enter human melanomaUISO-Mel-2 or human breast cancer MCF-7 cells. Yamada et al., PNAS99:14098-14103 (2002); Punj et al., Oncogene 23:2367-2378 (2004); Yamadaet al., Cell. Biol. 7:1418-1431 (2005). In addition, azurin from P.aeruginosa preferentially enters J774 murine reticulum cell sarcomacells, forms a complex with and stabilizes the tumor suppressor proteinp53, enhances the intracellular concentration of p53, and inducesapoptosis. Yamada et al., Infection and Immunity, 70:7054-7062 (2002).Azurin also caused a significant increase of apoptosis in humanosteosarcoma cells as compared to non-cancerous cells. Ye et al., AiZheng 24:298-304 (2003). Rusticyanin from Thiobacillus ferraoxidans canalso enter macrophages and induce apoptosis. Yamada et al., Cell Cycle3:1182-1187 (2004); Yamada et al., Cell. Micro. 7:1418-1431 (2005).Plastocyanin from Pharmidium laminosum and pseudoazurin formAchromobacter cycloclastes also are cytotoxic towards macrophages. U.S.Pat. Pub. No. 20060040269, published Feb. 23, 2006. Detailed studies ofvarious domains of the azurin molecule suggested that amino acids 50-77(p28) (SEQ ID NO: 13) represented a putative protein transduction domain(PTD) critical for internalization and subsequent apoptotic activity.Yamada et al., Cell. Microbial. 7:1418-1431 (2005), although possibleroutes of cellular entry were not identified

Azurin is now also known to have other pharmacologic activities oftherapeutic importance, it is known to inhibit angiogenesis in humanumbilical vascular endothelium cells (HUVECs). U.S. patent applicationSer. No. 11/488,693, filed Jul. 19, 2006. Azurin from P. aeruginosa isalso known for its ability to inhibit the growth of HIV-1 infection inperipheral blood mononuclear cells and to inhibit parasitemia ofmalaria-infected mammalian red blood cells. Chaudhari et al., CellCycle. 5: 1642-1648 (2006). Azurin from P. aeruginosa is also known tointerfere with the ephrin signaling system in various mammalian cellsand tissues. U.S. patent application Ser. No. 11/436,592, filed May 19,2006.

Azurin, and in particular, two peptides derived from azurin, an 18-merand a 28-mer, have therefore been found to be useful therapeutically anddiagnostically. However, the efficacy of a therapeutic agent in body ofthe patient is dependent on several factors. In addition to the activityof the therapeutic drug itself, there are also the pharmacokineticproperties of the therapeutic drug, and how it relates to the variousprocesses that take place after the drug is administered, i.e.,absorption, distribution, metabolism and excretion. Thesepharmacokinetic properties of the drug describe how and to what extentthese biological processes influence the efficacy of the administereddrug, and these properties include the drug half-life in the bloodstream, the hepatic first-pass metabolism of the drug, the volumedistribution of the drug, the degree of albumin binding of the drug,etc. Each of these pharmacokinetic properties can have a profound effecton the efficacy of the drug.

The site of absorption of the drug into the bloodstream of the patientdepends on the route of administration. For example, orally administereddrugs may be absorbed more at one site of the alimentary tract thananother site due to the chemical and physical nature of the drug.Absorption by parenteral administration, on the other hand, is not onlyfaster than oral administration, but the blood levels of the drug arefar more predictable because much less of the drug is lost, particularlyin intravenous administration. The bioavailability is the fraction ofthe administered drug that reaches the systemic circulation.

The distribution of the drug from the bloodstream into the extracellularfluid (interstitium) and/or cells of the tissues may be altered byvarious aspects of the drug. The distribution of the drug in the bodymay be expressed as the “volume distribution of the drug,” which is ahypothetical volume of liquid into which the drug is disseminated. Thestructure of the drug may influence the drug distribution in thathydrophobic drugs more readily move across most biological membranes,and thus may be distributed within cells of the tissues. A drug may alsobe bound to blood proteins and its passage into surrounding tissues thusdelayed. For example, when in the blood stream, naproxen is 99% bound toplasma proteins, penicillin G is 60% bound, amoxicillin only 20% boundand minoxidil is unbound. Howard C. Ansel et al., Pharmaceutical DosageForms and Delivery Systems 129 (Lippincott, Williams and Wilkins 1999).A bound drug is neither exposed to the body's detoxification processes,nor is it removed from the bloodstream by filtration through the renalglomeruli. The bound drug is referred to as the inactive portion whilethe unbound portion is considered the active portion. The bound portionof the drug serves as a reservoir of the drug that is then released intothe bloodstream in an unbound active form when the level of free drug isno longer sufficient to ensure protein saturation. Therefore, a drugthat is bound in the bloodstream will remain in the body for longerperiods of lime and will require a less frequent dosage.

The metabolism of the drug in the patient wilt also affect its efficacy.Many drugs undergo biotransformation before being excreted from thebody. The biotransformation of a drug may result in a form of the drugthat is more water soluble, ore ionized, less capable of bindingproteins in the plasma and tissues, less able to penetrate cellmembranes, and other aspects that make the drugs less pharmacologicallyactive. The biotransformed drug may therefore be rendered less toxic andmore readily excreted. There are four major ways by which drugs arebiotransformed: oxidation, reduction, hydrolysis, and conjugation.Oxidation reactions are primarily catalyzed by oxidases bound to theendoplasmic reticulum within the liver cells. Reduction reactions arecatalyzed by reductases primarily in the gut and liver. Hydrolyticbreakdown is catalyzed by esterases primarily in the liver. Glucuronideconjugation, the most common pathway of biotransformation of a drug,occurs by a combination of the drug with glucuronic acid, forming anionic form of the drug that is easily eliminated from the body.Christensen et al., J. Pharm. Pharmacol. 37:91-95 (1985). Otherbiotransformative processes that increase elimination includemethylation and acylation.

Excretion of the drug from the body may occur by various routes. Thekidney plays the dominant role of eliminating the drug in the urine.However, the drug can also be eliminated from the plasma through theliver. With drugs that are orally administered in particular, the livermay play an important role in determining the plasma half-life of thedrug.

SUMMARY OF THE INVENTION

One aspect of the invention provides an isolated modified cupredoxinderived peptide that is a variant, truncation or derivative of acupredoxin derived peptide. In some embodiments, the modificationincludes cyclization. In one embodiment the cyclization is enzymatic eyeligation. In another embodiment the cyclization creates a thioethercyclization. In another embodiment the thioether cyclization is formedby the addition of cysteine residues to dehydroalanine anddehydrobutrine residues. In another embodiment the dehydroalanine anddehydrobutrine residues originate from dehydration of serine andthreonine respectively. In another embodiment NisB dehydrates the serineand threonine.

In one embodiment, the isolated modified cupredoxin derived peptide hasimproved pharmacokinetic properties as compared to the unmodifiedcupredoxin derived peptide. The improved pharmacokinetic property may beone or more of the peptide (1) is less susceptible to biotransformationin the patient, (2) is excreted from the body of the patient at a slowerrate, (3) has increased stability of its tertiary structure and (4) haslonger plasma half-life.

Additionally, the isolated peptide may have at least one pharmacologicactivity of a cupredoxin. Specific pharmacologic activities of interestinclude (1) entering a mammalian cancer cell, (2) not enteringnon-cancerous mammalian cells, (3) entering pre-malignant mammaliancells, (4) killing mammalian cancer cells, (5) killing pre-malignantmammalian, cells, (6) inhibiting the growth of a mammalian cancer cell,(7) inhibiting HIV-1 infection, (8) inhibiting parasitemia ofmalaria-infected red blood cells, (9) interfering with ephrin signalingsystem and (10) inhibiting angiogenesis.

The modified cupredoxin derived peptide may be derived from a cupredoxinfrom Pseudomonas aeruginosa, Phormidium laminosum, Ulva pertussis,Thiobacillus ferraoxidans, Achromobacter cycloclastes, Pseudomonassyringae, Neisseria meningitidis, Vibrio parahaemolyticus, Bordetellabronchiseptica, Bordetella pertussis, Chloroflexus aurantiacus andNeisseria gonorrhoeae. The cupredoxin may be azurin, plastocyanin,rusticyanin, pseudoazurin, auracyanin stellacyanin, cucumber basicprotein or azurin-like protein. In specific embodiments, the cupredoxinmay be one of SEQ ID NOS: 1-12.

The isolated modified cupredoxin derived peptide may be a truncation ofthe cupredoxin. In specific embodiments, the peptide may be one of SEQID NOS: 13-47. On other specific embodiments, SEQ ID NOS: 1-12 are atleast about 90% identical to the isolated peptide.

In some embodiments, the isolated modified cupredoxin derived peptidemay be less susceptible to hydrolysis than the corresponding unmodifiedcupredoxin. Specifically, the isolated peptide may have one or moreasparagine or serine residues in the sequence of the cupredoxin derivedpeptide that are replaced with another amino acid residue, specificallya glutamic acid or threonine residue.

In some embodiments, the isolated modified cupredoxin derived peptide isless susceptible to deamidation. In specific embodiments, one or moreglycine residues of the cupredoxin derived peptide are replaced withanother amino acid residue, specifically a threonine or alanine residue.In some embodiments, one or more of the glycine residues in thecupredoxin derived peptide that are equivalent to residues 58 or 63 ofPseudomonas aeruginosa azurin (SEQ ID NO: 1) may be replaced. In anotherspecific embodiment, the isolated peptide may comprise SEQ ID NO: 30.

In some embodiments, the isolated modified cupredoxin derived peptide isless susceptible to oxidation. Specifically, the isolated peptide mayhave one or more methionine or cysteine residues of the cupredoxinderived peptide replaced with another amino acid residue, specifically aleucine or valine residue. In a specific embodiment, one or moremethionine residues of the cupredoxin derived peptide that areequivalent to residues 56 or 64 of Pseudomonas aeruginosa azurin (SEQ IDNO: 1) is replaced. In another specific embodiment, the isolated peptidemay comprise SEQ ID NO: 31 or SEQ ID NO: 32.

In some embodiments, the isolated modified cupredoxin derived peptidemay be less susceptible to diketopiperazine and pyroglutamic acidformation. Specifically, the isolated peptide may have a glycine residuein positions 1, 2 or 3 from the N-terminus of the cupredoxin derivedpeptide replaced with another amino acid residue. Further, the isolatedpeptide may have a proline residue in position 3 from the N-terminus ofthe cupredoxin derived peptide that is replaced with another amino acidresidue. Further, the isolated peptide may have an asparagine residue atthe N-terminus of the cupredoxin derived peptide replaced with anotheramino acid residue.

In some embodiments, the isolated modified cupredoxin derived peptidemay be less susceptible to racemization. Specifically, the isolatedpeptide may have one or more amino acid residues of the cupredoxinderived peptide replaced with the D-isomer of the amino acid residue. Inone specific embodiment, all of the amino acid residues of thecupredoxin derived peptide are replaced with the D-isomers of the aminoacid residues. In another specific embodiment, the isolated peptidecomprises SEQ ID NO: 45.

In some embodiments, the isolated modified cupredoxin derived peptidemay be less susceptible to degradation. Specifically, the N-terminus ofthe cupredoxin derived peptide may be acetylated. Further, theC-terminus of the cupredoxin derived peptide may be amidated. In onespecific embodiment, the isolated peptide is SEQ ID NO: 33.

In some embodiments, the isolated modified cupredoxin derived peptide ismodified to increase the stability of its tertiary structure.Specifically, the isolated peptide may be modified to increase thestability of a least one α-helix. In some embodiments, at least oneglycine, proline, serine, aspartic acid, alanine, threonine, valine,glutamine, asparagine, cysteine, histidine, lysine, and arginine aminoacid residue of the cupredoxin derived peptide is replaced with leucine,isoleucine, phenylalanine, glutamic acid, tyrosine, tryptophan ormethionine. In a specific embodiment, the replaced residue of thecupredoxin derived peptide may be within equivalent residues to residues53-56, 58-64 and 68-70 of P. aeruginosa azurin. In other specificembodiments, the glutamine at a residue equivalent to residue 57 of P.aeruginosa azurin may be replaced with a tryptophan residue, thethreonine at a residue equivalent to residue 52 of P. aeruginosa azurinmay be replaced with a tryptophan residue, the threonine at a residueequivalent to residue 61 of P. aeruginosa azurin may be replaced with atryptophan residue, and/or the glycine at a residue equivalent toresidue 63 of P. aeruginosa azurin is replaced with a tryptophanresidue. In other specific embodiments, the isolated peptide comprisesone of SEQ ID NOS: 34-44.

In other embodiments, the isolated peptide may have two or more lysineresidues of the cupredoxin derived peptide substituted withε-(3,5-dinitrobenzoyl)-lysine residues in an i(i+4) spacing.Specifically, the replaced residues of the cupredoxin derived peptidemay be within residues equivalent to residues 53-56, 58-64 and 68-70 ofP. aeruginosa azurin.

In other embodiments, the isolated peptide may have histidine-cysteineor histidine-histidine residue pairs substituted into the cupredoxinderived peptide at an i(i+4) spacing, and at least one of Cu, Zn, Cd andRu. In a specific embodiment, the isolated peptide may have the replacedresidues of the cupredoxin derived peptide within residues equivalent toresidues 53-56, 58-64 and 68-70 of P. aeruginosa azurin.

In another embodiment, the isolated peptide may have one or more pairsof native amino acid residues in the cupredoxin derived peptidesubstituted with α,α-disubstituted non-natural amino acids witholefin-bearing tethers that correspond to the native amino acids. Theisolated peptide may have the replaced residues of the cupredoxinderived peptide within residues equivalent to residues 53-56, 58-64 and68-70 of P. aeruginosa azurin.

In some embodiments, the isolated modified cupredoxin derived peptidemay have one or more PEG (polyethylene glycol) molecules covalentlybonded to the cupredoxin derived peptide. Specifically, the isolatedpeptide may have one or more PEG molecules is covalently bonded to oneor mote cysteine residues of the cupredoxin derived peptide. In specificembodiments, the isolated peptide may have one or more PEG molecules arecovalently bonded to one or more cysteine residues equivalent to one ormore of residues 3, 6, and 112 of Pseudomonas aeruginosa azurin (SEQ IDNO: 1). In another embodiment, a cysteine residue may be substitutedinto the cupredoxin derived peptide and may be covalently bonded to aPEG molecule.

In another embodiment, the isolated peptide may have one or more PEGmolecules covalently bonded to the cupredoxin derived peptide at alysine, cysteine, histidine, arginine, as panic acid, glutamic acid,serine, threonine, tyrosine, N-terminal amino group, or C-terminalcarboxylic acid. In specific embodiments, the isolated peptide has oneor more lysine residues or C-terminal carboxylic acids covalently bondedto a PEG molecule. In another embodiment, one or more lysine, cysteine,histidine, arginine, aspartic acid, glutamic acid, serine, threonine andtyrosine residues may be substituted into the cupredoxin derived peptideand may be covalently bonded to a PEG molecule.

In other embodiments, one or more PEG molecules may be covalently bondedto one or more amino groups of the cupredoxin derived peptide, orrandomly covalently bonded to the cupredoxin derived peptide.

The average molecular weight of the PEG molecules per cupredoxin derivedpeptide may be about 200 to about 100,000 daltons. The cupredoxinderived peptide may be covalently bonded to one or more branched PEGmolecules, specifically where the branched PEG molecule is about 50 kDa.The cupredoxin derived peptide may be covalently bonded to one or morelinear PEG molecules, specifically where the linear PEG molecule isabout 5 kDa.

Another aspect of the invention is a pharmaceutical composition whichmay comprise a modified cupredoxin derived peptide and apharmaceutically acceptable carrier.

Another aspect of the invention is a method to treat conditions sufferedby mammals which may comprise administering to the mammal atherapeutically effective amount of the modified cupredoxin derivedpeptides. In specific embodiments, the mammal is human.

Another aspect of the invention is an isolated peptide which comprises,or alternatively consists of, the amino acid sequenceX₁SX₂AADX₃X₄X₅VVX₆DX₇X₈ASGLDKDYLKPDX₉ (SEQ ID NO:48); wherein X₁ isselected from the group consisting of L and acetylated-L; X₂ is selectedfrom the group consisting of T and W; X₃ is selected from the groupconsisting of M, L and V; X₄ is selected from the group consisting of Qand W; X₅ is selected from the group consisting of G and A; X₆ isselected from the group consisting of T and W; X₇ is selected from thegroup consisting of G, T and W; X₈ is selected from the group consistingof M, L and V; and X₉ is selected from the group consisting of D andamidated-D.

Another aspect of the invention is an isolated peptide comprising, oralternatively consisting of, the amino acid sequenceX₁DPKLYDKDLGSAX₂X₃DX₄VVX₅X₆X₇DAAX₈SX₉ (SEQ ID NO:49); wherein X₁ isselected from the group consisting of D and acetylated-D; X₂ is selectedfrom the group consisting of M, L and V; X₃ is selected from the groupconsisting of G, T and W; X₄ is selected from the group consisting of Tand W; X₅ is selected from the group consisting of G and A; X₆ isselected from the group consisting of Q and W; X₇ is selected from thegroup consisting of M. L and V; X₈ is selected from the group consistingof T and W; and X₉ is selected from the group consisting of L andamidated-L.

Another aspect of the invention is an isolated peptide comprising, orconsisting of, the sequences of SEQ ID NOS: 50-3504, which arecupredoxin derived peptides modified using one or more of the techniquesand methods disclosed herein.

BRIEF DESCRIPTION OF THE SEQUENCES

SEQ ID NO: 1 is the amino acid sequence of wt-azurin from Pseudomonasaeruginosa.

SEQ ID NO; 2 is the amino acid sequence of plastocyanin from Phormidiumlaminosum.

SEQ ID NO; 3 is the amino acid sequence of rusticyanin from Thiobacillusferrooxidans.

SEQ ID NO: 4 is the amino acid sequence of pseudoazurin fromAchromobacter cycloclastes.

SEQ ID NO; 5 is the amino acid sequence of azurin from Pseudomonassyringae.

SEQ ID NO: 6 is the amino acid sequence of Laz from Neisseriagonorrhaeae.

SEQ ID NO: 7 is the amino acid sequence of the Laz from Neisseriameningitides.

SEQ ID NO; 8 is the amino acid sequence of the azurin from Vibrioparahaemolyticus.

SEQ ID NO: 9 is the amino acid sequence of the azurin from Bordetellabronchiseptica.

SEQ ID NO; 10 is the amino acid sequence of me auracyanin A fromChloroflexus aurantiacus

SEQ ID NO: 11 is the amino acid sequence of the auracyanin B fromChloroflexus aurantiacus.

SEQ ID NO: 12 is the amino acid sequence of the azurin from Bordetellapertussis.

SEQ ID NO: 13 is the amino acid sequence of the 50-77 amino acidfragment of wt-azurin (p28) from Pseudomonas aeruginosa.

SEQ ID NO: 14 is the amino acid sequence of the 50-67 amino acidfragment of wt-azurin (p18) from Pseudomonas aeruginosa.

SEQ ID NO: 15 is the amino acid sequence of the 36-128 amino acidfragment of wt-azurin from Pseudomonas aeruginosa.

SEQ ID NO: 16 is the amino acid sequence of the 36-89 amino acidfragment of wt-azurin from Pseudomonas aeruginosa.

SEQ ID NO: 17 is the amino acid sequence of the 36-77 amino acidfragment of wt-azurin from Pseudomonas aeruginosa

SEQ ID NO: 18 is the amino acid sequence of the 36-50 amino acidfragment of wt-azurin from Pseudomonas aeruginosa.

SEQ ID NO: 19 is the amino acid sequence of the 50-66 amino acidfragment of wt-azurin from Pseudomonas aeruginosa

SEQ ID NO: 20 is the amino acid sequence of the 67-77 amino acidfragment of wt-azurin from Pseudomonas aeruginosa.

SEQ ID NO: 21 is the amino acid sequence of the 57-89 amino acidfragment of auracyanin B of Chloroflexus aurantiacus.

SEQ ID NO: 22 is the amino acid sequence of the 50-77 amino acidfragment of azurin from Bordetella pertussis.

SEQ ID NO: 23 is the amino acid sequence of the 89-115 amino acidfragment of the Laz protein from Neisseria meningitidis.

SEQ ID NO: 24 is the amino acid sequence of the 53-70 amino acidfragment of azurin from Pseudomonas aeruginosa.

SEQ ID NO: 25 is the amino acid sequence of the 53-54 amino acidfragment of azurin from Pseudomonas aeruginosa.

SEQ ID NO: 26 is the amino acid sequence of the 51-77 amino acidfragment from azurin from Pseudomonas aeruginosa.

SEQ ID NO: 27 is the amino acid sequence of the 51-77 amino acidfragment from azurin from Pseudomonas syringae.

SEQ ID NO: 28 is the amino acid sequence of the is the 52-78 amino acidfragment from azurin from Vibrio parahaemolyticus.

SEQ ID NO: 29 is the amino acid sequence of the 51-77 amino acidfragment from azurin from Bordetella bronchiseptica.

SEQ ID NO: 30 is an artificial sequence for a variant form of the 50-77amino acid region of Pseudomonas aeruginosa azurin.

SEQ ID NO: 31 is an artificial sequence for a variant form of the 50-77amino acid region of Pseudomonas aeruginosa azurin.

SEQ ID NO: 32 is an artificial sequence for a variant form of the 50-77amino acid region of Pseudomonas aeruginosa azurin.

SEQ ID NO: 33 is an artificial sequence for a variant form of the 50-77amino acid region of Pseudomonas aeruginosa azurin.

SEQ ID NO: 34 is an artificial sequence for a variant form of the 50-77amino acid region or Pseudomonas aeruginosa azurin.

SEQ ID NO: 35 is an artificial sequence for a variant form of the 50-77amino acid region of Pseudomonas aeruginosa azurin.

SEQ ID NO: 36 is an artificial sequence for a variant form of the 50-77amino acid region of Pseudomonas aeruginosa azurin.

SEQ ID NO; 37 is an artificial sequence for a variant form of the 50-77amino acid region of Pseudomonas aeruginosa azurin.

SEQ ID NO: 38 is an artificial sequence for a variant form of the 50-77amino acid region of Pseudomonas aeruginosa azurin.

SEQ ID NO: 39 is an artificial sequence for a variant form of the 50-77amino acid region of Pseudomonas aeruginosa azurin.

SEQ ID NO: 40 is an artificial sequence for a variant form of the 50-77amino acid region of Pseudomonas aeruginosa azurin.

SEQ ID NO: 41 is an artificial sequence for a variant form of the 50-7amino acid region of Pseudomonas aeruginosa azurin.

SEQ ID NO: 42 is an artificial sequence for a variant form of the 50-77amino acid region of Pseudomonas aeruginosa azurin.

SEQ ID NO: 43 is an artificial sequence for a variant form of the 50-77amino acid region of Pseudomonas aeruginosa azurin.

SEQ ID NO: 44 is an artificial sequence for a variant form of the 50-77amino acid region of Pseudomonas aeruginosa azurin.

SEQ ID NO: 45 is an artificial sequence for a variant form of the 50-77amino acid region of Pseudomonas aeruginosa azurin.

SEQ ID NO: 46 is a conserved amino acid sequence from azurins where D isaspartic acid, G is glycine, Y is tyrosine, K is lysine and X is anyamino acid.

SEQ ID NO: 47 is a conserved amino acid sequence from azurins where D isaspartic acid, G is glycine, Y is tyrosine, K is lysine and X is anyamino acid.

SEQ ID NO: 48 is an artificial sequence of modifications to azurin 50-77of Pseudomonas aeruginosa.

SEQ ID NO: 49 is an artificial sequence of modifications to the D-isomerof azurin 50-77 of Pseudomonas aeruginosa.

SEQ ID NOS: 50-3504 are sequences for variant forms of the 50-77 aminoacid region of Pseudomonas aeruginosa azurin.

SEQ ID NO: 3505 is the amino acid sequence of Pep42, a cyclic 13-meroligopeptide.

SEQ ID NO: 3506 is the amino acid sequence of the 66-77 amino acidfragment (p12) of wt-azurin from Pseudomonas aeruginosa.

SEQ ID NO; 3507 is a sequence for a variant form of the 50-77 amino acidregion of Pseudomonas aeruginosa azurin.

SEQ ID NO: 3508 is a sequence for a variant form of the 50-77 amino acidregion of Pseudomonas aeruginosa azurin.

SEQ ID NO: 3509 is a sequence for a variant form of the 50-77 amino acidregion of Pseudomonas aeruginosa azurin.

SEQ ID NO: 3510 is a sequence for a variant form of the 50-77 amino acidregion of Pseudomonas aeruginosa azurin.

SEQ ID NO: 3511 is a sequence for a variant form of the 50-77 amino acidregion of Pseudomonas aeruginosa azurin.

SEQ ID NO: 3512 is a sequence for a variant form of the 50-77 amino acidregion of Pseudomonas aeruginosa azurin.

SEQ ID NO; 3513 is a sequence for a variant form of the 50-77 amino acidregion of Pseudomonas aeruginosa azurin.

SEQ ID NO: 3514 is a sequence for a variant form of the 50-77 amino acidregion of Pseudomonas aeruginosa azurin.

SEQ ID NO: 3515 is a sequence for a variant form of the 50-77 amino acidregion of Pseudomonas aeruginosa azurin.

SEQ ID NO: 3516 is a sequence for a variant form of the 50-77 amino acidregion of Pseudomonas aeruginosa azurin.

SEQ ID NO: 3517 is a sequence for a variant form of the 50-77 amino acidregion of Pseudomonas aeruginosa azurin.

SEQ ID NO: 3518 is a sequence for a variant form of the 50-77 amino acidregion of Pseudomonas aeruginosa azurin.

SEQ ID NO: 3519 is a sequence for a variant form of the 50-77 amino acidregion of Pseudomonas aeruginosa azurin.

SEQ ID NO: 3520 is a sequence for a variant form of the 50-77 amino acidregion of Pseudomonas aeruginosa azurin.

SEQ ID NO: 3521 is a sequence for a variant form of the 50-77 amino acidregion of Pseudomonas aeruginosa azurin.

SEQ ID NO: 3522 is a sequence for a variant form of the 50-77 amino acidregion of Pseudomonas aeruginosa azurin.

SEQ ID NO: 3523 is a sequence for a variant form of the 50-77 amino acidregion of Pseudomonas aeruginosa azurin.

SEQ ID NO: 3524 is a sequence for a variant form of the 50-77 amino acidregion of Pseudomonas aeruginosa azurin.

SEQ ID NO: 3525 is a sequence for a variant form of the 50-77 amino acidregion of Pseudomonas aeruginosa azurin.

SEQ ID NO: 3526 is the amino acid sequence of the 60-77 amino acidfragment (p18b) of wt-azurin from Pseudomonas aeruginosa.

SEQ ID NO: 3527 is the amino acid sequence of Arg-8.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts the images of whole mouse scans of mice that have beeninjected with labeled p18 (SEQ ID NO: 14). IRDye® labeled p18 (SEQ IDNO: 14) (125 μg) was injected intravenously and athymic mice werescanned at indicated time periods for detection of labeled dye in tumorsand organs using the Odyssey® Infrared Imaging System.

FIG. 2 depicts the images from whole mouse and organs scans of mice thathave been injected with labeled p18 (SEQ ID NO: 14), 125 μg IRDye®labeled p18 (SEQ ID NO; 14) 120 h post-injection i.v. (immediatelybefore sacrifice). Excised organs scanned and shown on right. p18 (SEQID NO: 14) signal was seen from kidneys and Mel-2 tumors.

FIG. 3. Mel-2 subcutaneous tumor with 125 ug IRDye® labeled p18 (SEQ IDNO: 14) administered i.v. 3 weeks after Mel-2 cells were injected, andOdyssey® infrared scan was performed 48 hours later. Images recordedwith the 800 nm channel represent specific p18 (SEQ ID NO; 14) signalfrom IRDye®, and those with the 700 am channel represent background. p18(SEQ ID NO: 14) signal was seen from kidneys and Mel-2 tumors.

FIGS. 4 (A) and (B). Azurin truncation with alpha-helical structure andthe results of a 70 ns simulation.

FIG. 5. Measurement of thioether bridge positions in p28 (SEQ ID) NO:13) based on distances between Cα atoms in a simulated structure.

FIGS. 6A-6D. FIGS. 6A and 6B are photographs showing penetration ofazurin derived peptides into cancer cell lines of diverse histogenesisand their normal counterparts. FIGS. 6A and 6B are photographs showingpenetration of Alexafluor 568 labeled p28 (SEQ ID NO: 13) and p18 (SEQID NO: 14), respectively, after 2 hrs at 37° C. The cationic Arg-8 (SEQID NO: 3527) was used as a control. FIG. 6C are graphs depicting flowcytometric analysis of the penetration of Alexafluor 568 labeled as p28(SEQ ID NO: 13) or p18 (SEQ ID NO: 14) into the same cell lines after 2hrs at 37° C. FIG. 6D are graphs depicting fold increase overfluorescence from normal cells. Similar observations of p28 (SEQ ID NO:13) or p18 (SEQ ID NO: 14) entry into 4 melanoma cell lines show aseveral fold increase over fluorescence from normal cells.

FIGS. 7 (A) and (B). Depicts photographs showing entry of azu 60-77(p18b) (SEQ ID NO: 3526) and azu 66-77 (p12) (SEQ ID NO: 3506) intocancer and normal cells. Cells were incubated with alexafluor 568labeled p18b (SEQ ID NO: 3526) (A) or p12 (SEQ ID NO: 3506) (B) at 37°C. for 2 hrs and images recorded by confocal microscopy.

FIGS. 8 (A) and (B). Graphs depicting cellular membrane toxicity ofazurin and its peptides. FIG. 8(A) is a graph showing LDH leakage assayof UISOMel-2 cells exposure for 10 min to different concentrations ofp28 (SEQ ID NO: 13), p18 (SEQ ID NO: 14) and azurin at 37° C. A standardlysis buffer (cytotox-one reagent) was included as a positive control.Changes in fluorescence following exposure were measured at k,x 560 nmand kem 590 nm. Lysis buffer was defined as 100% LDH release. Datarepresent % of positive fluorescence of control. Data are shown asmean±SEM. FIG. 8B is a graph showing Hemoglobin leakage from humanerythrocytes incubated with p28 (SEQ ID NO: 13), p18 (SEQ ID NO: 14) andazurin. Human erythrocytes were incubated with peptide for 30 min at 37°C. and absorbance at 540 nm determined. Hemoglobin release following0.1% Triton X-100 was defined as 100% hemoglobin release. Data representmean±SEM of triplicate determinations.

FIGS. 9 (A), (B), (C) and (D) Depicts photographs showing temperaturedependent and competitive internalization of p28 (SEQ ID NO: 13) and p18(SEQ ID NO: 14) into UISO-Mel-2 cells. Penetration of Alexafluor 568labeled p28 (SEQ ID NO: 13) (A) or p18 (SEQ ID NO: 14) (B) at 2011M wasevaluated by confocal microscopy at different temperatures. (C) and (D)Confocal analysis of entry of Alexafluor 568 labeled p28 (SEQ ID NO: 13)(C) or p18 (SEQ ID NO: 14) (D) at 5 μM into UISO-Mel-2 cells alter 30min at 37° C. in the presence/absence of unlabeled peptide (200 foldexcess).

FIGS. 10 (A), (B), (C) and (D). (A) Depicts photographs showing confocalanalysis of 28, p18 (SEQ ID NO; 14) (20 μM) and Arg-8 (SEQ ID NO: 3527)(10 μM) entry into UISO-Mel-2 cells after 1 hr at 37° C. in thepresence/absence of heparin sulfate (100 μg/ml). (B) Graphs showing flowcytometric analysis of p28 (SEQ ID NO: 13) or p18 (SEQ ID NO: 14) entryin the presence of inhibitors. Cell fluorescence intensity in theabsence of inhibitor (control) was considered as 100%. (C) Graphsdepicting FRCS analysis of p28 (SEQ ID NO: 13) and p18 (SEQ ID NO; 14)entry into fibroblasts in presence of inhibitors. (D) Depictsphotographs showing colocalization of p18 (SEQ ID NO: 14) and p28 (SEQID NO: 13) with caveolin I (Panel I). UISO-Mel-2 cells were incubatedwith Alexafluor 568 labeled p18 (SEQ ID NO: 14) or p28 (SEQ ID NO: 13)(20 μM) or media for 2 hrs at 37° C. Cells were fixed and processed foranti-caveolin 1 immunostaining. Confocal analysis of entry of Alexafluor568 labeled p18 (SEQ ID NO: 14) or p28 (SEQ ID NO: 13) (20 μM) intoUISO-Mel-2 cells after 2 hrs at 37° C. followed by antigolgin 97antibodies (Panel 2). Colocalization of Alexafluor 568 labeled azurin,p28 (SEQ ID NO: 13) and p18 (SEQ ID NO: 14) (red) with mitotracker(green) (Panel 3) and Lysotracker (green) (Panel 4) dyes in UISO-Mel-2cells. Cells were incubated at 37° C. with 20 μM azurin, p28 (SEQ ID NO:13), p18 (SEQ ID NO: 14) or media only. After 90 min incubation,mitotracker/lysotracker probes were added and cells incubated for 30min. Cells were counterstained with DAPI (blue). Colocalization ofazurin, p28 (SEQ ID NO; 13) or p18 (SEQ ID NO: 14) appears as a yellowflorescence.

FIGS. 11 (A) and (B). Graphs depicting UISO-Mel-2 cells that wereincubated with increasing concentrations of azurin, p28 (SEQ ID NO: 13),or p18 SEQ ID NO: 14) at 37° C. for 72 hrs. MTT (A); Direct cell count(B). Cell viability (MTT) or cell number in control wells wereconsidered as 100%. Data represent mean±SEM.

FIG. 12, (A) through (H). Depict photographs showing uptake of compoundsby cells, taken using a confocal microscope after treatment of cellswith proteins and/or buffer. (A) Human brain tumor LN-229 cells werepretreated with 20 μM of unlabeled proteins or PBS buffer for 1 hours,then washed three times using PBS buffer. All buffer was discarded andthen 20 μM of Alex568-Paz was added for 30 minutes at 37° C. (B) TheLN-229 cells were then treated with 20 μM of unlabeled proteins or PBSbuffer and 20 μM of Alex568-Paz for 30 minutes at 37° C. (C) Anothergroup of human brain tumor LN-229 cells were pretreated with 10 μMunlabeled proteins or PBS buffer for 2 hours, then washed three timesusing PBS buffer. All buffer was discarded and then 10 μM of Alex568-Pazwas added for 30 minutes at 37° C. (D) The LN-229 cells were thentreated with 10 μM unlabeled proteins or PBS buffer and 10 μM ofAlex568-Paz for 30 minutes at 37° C. (E) Human brain tumor LN-229 cellswere treated with 20 μM of unlabeled proteins or PBS buffer and 20 μM ofAlex568-Paz for 30 minutes at 37° C. (F) Human brain tumor LN-229 cellswere treated with 20 μM of Alex568-11.8 for 30 minutes at 37° C. (G)Human brain tumor LN-229 cells were treated with 20 μM Alex568-proteinsfor 30 minutes at 37° C. (H) Human breast adenocarcinoma MCF-7 cellswere treated with 20 μM of Alex568-proteins for 30 minutes at 37° C.

FIG. 13, (A) through (Q. Graphs and charts depicting peptide binding andentry into cells. (A) UISO-Mel-2 or fibroblast cells (3×10⁵ cells) weresuspended in MEME media without phenol red. Reactions were started byadding Alexafluor 568-conjugated p28 (SEQ ID NO: 13) at 10, 50, 100,150, 250, 300 and 400 μM for 30, 60, 90 and 120 sec on ice. Cells wereanalyzed by flow cytometry. (B) The K_(m) and V_(max) were calculated byplotting peptide concentration (μM) vs. velocity (MFI/sec). (C) Peptidebinding and entry was determined using whole Mel2 cells (50,000cells/ml), were incubated for 30 min at 37° C. with increasingconcentrations (0-175 nM) of radiolabeled azurin in the presence/absenceof 1000 fold excess of unlabeled p28 (SEQ ID NO: 13), or azurin, andradioactivity remaining in the cell pellet counted using a gammacounter. Radioactivity in cells incubated with ¹²⁵I azurin alone wasconsidered total binding; radioactivity in the presence of unlabeledazurin or p28 (SEQ ID NO: 13) was considered nonspecific binding.Specific binding was determined by subtracting nonspecific binding fromtotal binding and Scatchard plots generated.

FIG. 14, (A) through (C). Depict side and back photographs of mice withmelanoma MEL-23 tumors taken alter injection with p28 (SEQ ID NO: 13)dye complex at 60 μmolar concentration in 250 μL scans and afterinjection with control PBS at (A) 24 hours and (B) 48 hours. (C) depictsside and back photographs of mice with melanoma MEL-23 tumors takenafter injection with p28 (SEQ ID NO: 13) at 200 μM concentration at 24and 48 hours.

FIG. 15, (A) through (C). Depict side and back photographs of mice withmelanoma MEL-23 tumors taken after injection with p18 (SEQ ID NO; 14) at60 μmolar concentration at (A) 17 hours, (B) 24 hours, and (C) 46 hours.(C) also depicts photographs of mouse organs, including the heart, lung,liver, kidney, spleen, and brain, taken 46 hours after injection of p18(SEQ ID NO: 14).

FIGS. 16, (A) and (B). (A) Depicts side and back photographs of micewith tumors taken 12 hours after injection with p18 (SEQ ID NO: 14), p28(SEQ ID NO: 13), and Arg-8 (SEQ ID NO: 3527) at 60 μmolar concentration.(B) Depicts photographs of mouse organs, including mouse brains, taken12 hours after injection with p18 (SEQ ID NO: 14), p28 (SEQ ID NO: 13),and Arg-8 (SEQ ID NO: 3527).

FIGS. 17, (A) and (B). (A) Depicts side and back photographs of micewith melanoma MEL-6 tumors taken 40 hours after injections of 600 μMconcentrations of p18 (SEQ ID NO; 14) and Arg-8 (SEQ ID NO: 3527) intotail veins. Animals treated with p18 (SEQ ID NO: 14) received 0.5million cells, and animals treated with Arg-8 (SEQ ID NO: 3527) received1 million cells. (B) Depicts photographs of mouse organs taken 40 hoursafter injections of 600 μM concentrations of p18 (SEQ ID NO: 14) andArg-8 (SEQ ID NO; 3527).

FIGS. 18, (A) and (B). (A) Depicts side and back photographs of micewith melanoma MEL-23 tumors taken 16 hours after injections of 60 μMconcentrations of p28 (SEQ ID NO: 13), p18 (SEQ ID NO: 14), and Arg-8(SEQ ID NO: 3527). (B) Depicts side and back photographs of mice withmelanoma MEL-23 tumors token 24 hours after injections of 60 μMconcentrations of p28 (SEQ ID NO: 13), p18 (SEQ ID NO: 14), and Arg-8(SEQ ID NO: 3527).

FIG. 19. Depicts photographs of mouse organs taken 48 hours alterinjection of 60 μM concentrations of p28 (SEQ ID NO: 13) and p18 (SEQ IDNO: 14) dye peptide complex into mice with melanoma MEL-23.

FIG. 20. Depicts photographs of mouse organs taken 24 hours afterinjection of 60 μM concentrations of p28 (SEQ ID NO: 13) into mice withMEL-23 tumors and organs.

FIG. 21. Depicts side and back photographs of mice with melanoma MEL-23tumors taken 16 hours after injections of 60 μM concentrations of p28(SEQ ID NO: 13) and Arg-8 (SEQ ID NO: 3527).

FIG. 22. Depicts side and back photographs of mice with melanoma MEL-23tumors taken 16 hours after injections of 60 μM concentrations of p18(SEQ ID NO: 14).

FIG. 23. Depicts side photographs of mice with rumors taken 10 and 24hours after high dose treatment with 240 μM concentrations of p18 SEQ IDNO: 14), p28 (SEQ ID NO: 13), and Arg-8 (SEQ ID NO: 3527).

FIG. 24. Depicts side and back photographs of mice with MCF-tumors andorgans taken 28 hours after high dose treatment with 240 μMconcentrations of p18 (SEQ ID NO: 14), p28 (SEQ ID NO: 13), and Arg-8(SEQ ID NO: 3527). Also depicts photographs of mouse organs with MCF-7taken 28 hours after high dose treatment with 240 μM concentrations ofp18 (SEQ ID NO: 14), p28 (SEQ ID NO: 13), and Arg-8 (SEQ ID NO: 3527).

FIG. 25. Depicts side and back photographs of mice with tumors taken 50hours after high dose treatment with 240 μM concentrations of p18 (SEQID NO: 14), p28 (SEQ ID NO: 13), and Arg-8 (SEQ ID NO: 3527).

FIG. 26. Depicts photographs of mouse organs taken 24 hours afterinjection of 120 μM concentrations of p18 (SEQ ID NO: 14), p28 (SEQ IDNO: 13), and Arg-8 (SEQ ID NO: 3527) into the tail veins of mice withHCT-116 tumors and organs.

FIGS. 27, (A) and (B). (A) Depicts photographs of mouse organs taken 24hours after injection of 120 μM concentrations of p18 (SEQ ID NO: 14),p28 (SEQ ID NO: 13), and Arg-8 (SEQ ID NO: 3527) into the tail veins ofmice with HCT-116 tumors and organs. (B) Depicts side photographs ofmice with HCT-116 tumors taken 21 hours after injection of 120 μMconcentrations of p18 (SEQ ID NO: 14), p28 (SEQ ID NO: 13), and Arg-8(SEQ ID NO: 3527) into their tail veins.

FIG. 28, (A) and (B). (A) Depicts side and back photographs of mice withHCT-116 24 hours after injection with 120 μM concentrations of p28 (SEQID NO: 13), 47 days after injection of 1 million cells into tail veins.(B) Depicts photographs of mouse organs taken from mice with HCT-116 4hours after injection with 120 μM concentrations of p28 (SEQ ID NO: 13),47 days after injection of 1 million cells into tail veins.

FIG. 29. Depicts photographs of organs from MEL-6 mice taken 24 hoursafter treatment with 120 μM concentrations of p18 (SEQ ID NO: 14), p28(SEQ ID NO: 13), and Arg-8 (SEQ ID NO: 3527).

FIGS. 30, (A) and (B). (A) Depicts side and hack photographs of MEL-6mice taken 22 hours after injection of 120 μM concentrations of p18 (SEQID NO; 14), p28 (SEQ ID NO: 13), and Arg-8 (SEQ ID NO; 3527), and 60 60μM concentration of Arg-8 (SEQ ID NO: 3527). (B) Depicts photographs ofMEL-6 mouse organs after treatment with 120 μM concentrations of p18(SEQ ID NO: 14), p28 (SEQ ID NO: 13), and Arg-8 (SEQ ID NO: 3527), and60 μM concentration of Arg-8 (SEQ ID NO: 3527).

FIGS. 31, (A) and (B). (A) Depicts photographs of organs from HT-1080mice taken 22 hours alter treatment with 60 and 120 μM concentrations ofp18 (SEQ ID NO: 14), p28 (SEQ ID NO; 13), and Arg-8 (SEQ ID NO: 3527).(B) Depicts side-by-side photographs of brains from HT-1080 mice taken22 hours after treatment with 60 and 120 μM concentrations of p18 (SEQID NO: 14), p28 (SEQ ID NO: 13), and Arg-8 (SEQ ID NO: 3527),demonstrating the differences between uptake of p18 (SEQ ID NO: 14) andp28 (SEQ ID NO: 13) into the brain.

FIG. 32. Depicts side and back photographs of HT-1080 mice duringDoxorubicin vs. p28 (SEQ ID NO: 13) study taken 16 hours after treatmentwith 60 and 120 μM concentrations of p18 (SEQ ID NO: 14), p28 (SEQ IDNO: 13), and Arg-8 (SEQ ID NO: 3527).

FIG. 33, (A) and (8). (A) Depicts photographs of organs from HT-1080mice taken 22 hours after treatment with 60 and 120 μM concentrations ofp28 (SEQ ID NO: 13) and Arg-8 (SEQ ID NO: 3527). (B) Depictsside-by-side photographs of brains from HT-1080 mice taken 22 hoursafter treatment with 60 and 120 μM concentrations of p28 (SEQ ID NO: 13)and Arg-8 (SEQ ID NO: 3527).

FIGS. 34, (A) and (B)-(A) Depicts photographs of organs from HT-1080mice taken 22 hours after treatment with 60 and 120 μM concentrations ofp18 (SEQ ID NO: 14) and Arg-8 (SEQ ID NO: 3527). (B) Depictsside-by-side photographs of brains from HT-1080 mice taken 22 hoursafter treatment with 60 and 120 μM concentrations of p18 (SEQ ID NO: 14)and Arg-8 (SEQ ID NO: 3527).

FIG. 35, (A) through (E). Depicts photographs of HT-1080 mice with lungmetastases treated via their tail veins with (A) 3 mg/kg Doxorubicin IP,3 treatments; (B) 5 mg/kg IP p28 (SEQ ID NO: 13) daily; (C) PBS control,PBS IP daily; (D) 10 mg/kg IP p28 (SEQ ID NO: 13) daily; (E) 20 mg/kg IPdaily.

FIG. 36, (A) and (8). (A) Depicts photographs of organs from HT-1080mice in an animal study, whereby 1×10⁶ cells are injected into tailveins (43 days) and all treated mice have lung metastases, taken 24 and26 hours after 60 μM concentrations of p28 (SEQ ID NO: 13) injected intotail veins. Animal 6982 was dead when photographed. (B) Depicts side andback photographs of HT-1080 mice in an animal study, whereby 1×10⁶ cellsare injected into tail veins (43 days), taken 22 hours after 60 μMconcentrations of p28 (SEQ ID NO: 13) injected into tail veins. Animal6982 was dead when photographed.

FIG. 37. Depicts side and back photographs of HT-1080 mice in an animalstudy, whereby 1×10⁶ cells are injected into tail veins (43 days), taken26 hours alter 60 μM concentrations of p28 (SEQ ID NO; 13) injected intotail veins.

FIGS. 38, (A) and (B). Depicts photographs of (A) organs from mice and(B) back views of mice in Balb-C peptide study taken 12 hours aftertreatment with 60 and 120 μM concentrations of p18 (SEQ ID NO: 14), p28(SEQ ID NO; 13), and Arg-8 (SEQ ID NO: 3527).

FIGS. 39, (A) and (B). Depicts photographs of (A) organs from mice and(B) side views of mice in Balb-C peptide study token 24 hours altertreatment with 60 and 120 μM concentrations of p18 (SEQ ID NO; 14), p28(SEQ ID NO: 13), and Arg-8 (SEQ ID NO: 3527).

FIG. 40. Depicts side and back photographs of MEL-6 mice (0.5 millioncells injected via tail vein) 16 hours after injection into tail veinsof 60 μM concentrations of p18 (SEQ ID NO: 14) and Arg-8 (SEQ ID NO:3527).

FIG. 41, (A) through (D). Depicts photographs of mouse organs, andspecifically mouse brains, after treatment with p18 (SEQ ID NO: 14) andp28 (SEQ ID NO; 13).

FIG. 42. Depicts photographs of organs from MEL-6 mice taken 24 hoursafter treatment with p28 (SEQ ID NO: J3), p18 (SEQ ID NO: 14), and Arg-8(SEQ ID NO: 3527).

FIG. 43, (A) through (C*). (A) Depicts side and back photographs ofMEL-6 mice 3 hours after injection with 60 μM concentrations of p18 (SEQID NO; 14), p28 (SEQ ID NO: 13), and Arg-8 (SEQ ID NO: 3527). (B)Depicts side and back photographs of MEL-6 mice, and photographs oforgans from MEL-6 mice, taken 22 hours after injection with 60 μMconcentrations of p18 (SEQ ID NO: 14), p28 (SEQ ID NO: 13), and Arg-8(SEQ ID NO: 3527). (C) Depicts photographs of organs from MEL-6 mice 24hours after injection with 60 μM concentrations of p18 (SEQ ID NO: 14),p28 (SEQ ID NO: 13), and Arg-8 (SEQ ID NO; 3527).

FIGS. 44, (A) and (B). Depict uptake of p18 (SEQ ID NO: 14) and p28 (SEQID NO: 13) into (A) mouse brains and (B) mouse organs).

FIG. 45. Depicts side and back photographs of MEL-6 mice in studywhereby 0.5 million cells injected I.V. into tail vein (44 days post),taken 120 hours after injection into tail vein of 24 μM concentrationsof p18 (SEQ ID NO: 14) and Arg-8 (SEQ ID NO; 3527).

FIG. 46. Depicts photographs of organs from MEL-6 mice taken 168 hoursafter treatment with p18 (SEQ ID NO: 14).

FIG. 47. Depicts side and back photographs of MEL-6 mice taken 72 hrsafter injection of Arg-8 (SEQ ID NO: 3527) and p18 (SEQ ID NO: 14), 41days post injection of cells.

FIG. 48. Depicts back photographs of mice taken after injection of Arg-8(SEQ ID NO: 3527) and p18 (SEQ ID NO: 14).

FIG. 49. Depicts side and front photographs of mice taken 3, 24, and 48hours after injection of Arg-8 (SEQ ID NO: 3527) and p18 (SEQ ID NO:14).

DETAILED DESCRIPTION OF THE EMBODIMENTS Definitions

As used herein, the term “cell” includes both the singular or the pluralof the term, unless specifically described as a “single cell.”

used herein, the terms “polypeptide,” “peptide,” and “protein” are usedinterchangeably to refer to a polymer of amino acid residues. The termsapply to amino acid polymers in which one or more amino acid residuesare an artificial chemical analogue of a corresponding naturallyoccurring amino acid. The terms also apply to naturally occurring aminoacid polymers. The terms “polypeptide,” “peptide,” and “protein” arealso inclusive of modifications including, but not limited to,glycosylate on, lipid attachment, sulfation, gamma-carboxylation ofglutamic acid residues, hydroxylation and ADP-ribosylation. It will beappreciated that polypeptides are not always entirely linear. Forinstance, polypeptides may be branched as a result of ubiquitination andthey may be circular (with or without branching), generally as a resultof post-translation events, including natural processing event andevents brought about by human manipulation which do not occur naturally.Circular, branched and branched circular polypeptides may be synthesizedby non-translation natural process and by entirely synthetic methods aswell. A synthetic peptide is one made without the aid of cellularcomponents. Synthetic methods to make peptides are well known in the artand are commercially available. Further, this invention contemplates theuse of both the methionine-containing and the methionine-less aminoterminal variants of the protein of the invention.

As used herein, the term “condition” includes anatomic and physiologicaldeviations from the normal that constitute an impairment of the normalstate of the living animal or one of its parts, that interrupts ormodifies the performance of the bodily functions.

As used herein, the term “inhibit cell growth” means the slowing orceasing of cell division and/or cell expansion. This term also includesthe inhibition of cell development or increases in cell death.

As used herein, the term “suffering from” includes presently exhibitingthe symptoms of a condition, having a condition even without observablesymptoms, in recovery from a condition, and recovered from a condition.

A used herein, the term “treatment” includes preventing, lowering,stopping, or reversing the progression or severity of the condition orsymptoms associated with a condition being treated. As such, the term“treatment” includes medical, therapeutic, and/or prophylacticadministration, as appropriate.

A “therapeutically effective amount” is an amount effective to prevent,lower, stop or reverse the development of, or to partially or totallyalleviate a particular condition, or the existing symptoms of aparticular condition for which the subject being treated. Determinationof a therapeutically effective amount is well within the capability ofthose skilled in the art.

As used herein, the term “pharmacologic activity” means the effect of adrug or other chemical on a biological system. The effect of chemicalmay be beneficial (therapeutic) or harmful (toxic). The pure chemicalsor mixtures may be of natural origin (plant, animal, or mineral) or maybe synthetic compounds.

As used herein, the term “premalignant” means precancerous, or beforeabnormal cells divide without control.

As used herein, the term “pharmacokinetic property” refers to aparameter that describes the disposition of an active agent or drug inan organism or host. Representative pharmacokinetic properties include;plasma half-life, hepatic first-pass metabolism, volume of distribution,degree of blood serum protein, e.g. albumin, binding, etc.

As used herein, the term “plasma hall-life” refers to the time forone-half of an administered drug to be eliminated from the plasma of thepatient through biological processes, e.g., biometabolism, excretion,etc.

As used herein, the term “volume of distribution” refers to thedistribution and degree of retention of a drug throughout the variouscompartments of an organisms, e.g. intracellular and extracellularspaces, tissues and organs, etc. This factor is expressed as the“apparent volume of distribution,” or V_(d), which is the estimatedvolume of the body into which the drug has distributed. A large Vdsuggests that the drug has distributed more broadly throughout the bodyand may be associated with the longer half-life because a lesser portionof the drug will be in the plasma and thus delivered to the eliminationpoints, the kidney and the liver.

As used herein, the term “degree of blood serum binding” refers to thepropensity of a drug to be bound by a blood serum protein, such asalbumin.

As used herein, the term “efficacy” refers to the effectiveness of aparticular active agent for its intended purpose, i.e. the ability of agiven active agent to cause its desired pharmacologic effect.

As used herein, the term “specific activity” refers to the amount ofproduct formed by an enzyme in a given amount of time under givenconditions per milligram of enzyme. Specific activity is equal to therate of reaction multiplied by the volume of reaction divided by themass of enzyme. In the case of a transport peptide, the specificactivity will be the amount of transport peptide or transportpeptide-cargo complex internalized into a cell in a given amount of timeunder given conditions per milligram of transport peptide or transportpeptide-cargo complex.

The term “substantially pure,” as used herein, when used to modify aprotein or other cellular product of the invention, refers to, forexample, a protein isolated from the growth medium or cellular contents,in a form substantially free of, or unadulterated by, other proteinsand/or active inhibitory compounds. The term “substantially pure” refersto a factor in an amount of at least about 75%, by dry weight, ofisolated fraction, or at least “75% substantially pure.” Morespecifically, the term “substantially pure” refers to a compound of atleast about 85%, by dry weight, active compound, or at least “85%substantially pure.” Most specifically, the term “substantially pure”refers to a compound of at least about 95%, by dry weight, activecompound, or at least “95% substantially pure.” The term “substantiallypure” may also be used to modify a synthetically made protein orcompound, where, for example, the synthetic protein is isolated from thereagents and by-products of the synthesis reaction(s).

The term “pharmaceutical grade.” as used herein, when referring to apeptide or compound of the invention, is a peptide or compound that isisolated substantially or essentially from components which normallyaccompany the material as it is found in its natural state, includingsynthesis reagents and by-products, and substantially or essentiallyisolated from components that would impair its use as a pharmaceutical.For example, a “pharmaceutical grade” peptide may be a isolated awayfrom any carcinogen. In some instances, “pharmaceutical grade” may bemodified by the intended method of administration, such as “intravenouspharmaceutical grade,” in order to specify a peptide or compound that issubstantially or essentially isolated from any substance that wouldrender the composition unsuitable for intravenous administration to apatient. For example, an “intravenous pharmaceutical grade” peptide maybe isolated from detergents, such as SDS, and anti-bacterial agents,such as azide.

The phrases “isolated,” “purified” or “biologically pure” refer tomaterial which is substantially or essentially free from componentswhich normally accompany the material as it is found in its nativestate. Thus, isolated peptides in accordance with the inventionpreferably do not contain materials normally associated with thepeptides in their in situ environment. An “isolated” region refers to aregion that does not include the whole sequence of the polypeptide fromwhich the region was derived. An “isolated” nucleic acid, protein, orrespective fragment thereof has been substantially removed from its invivo environment so that it may be manipulated by the skilled artisan,such as but not limited to nucleotide sequencing, restriction digestion,site-directed mutagenesis, and subcloning into expression vectors for anucleic acid fragment as well as obtaining the protein or proteinfragment in substantially pure quantities.

The term “wild-type,” as used herein to refer to a peptide, mean thatthe peptide has the same sequence as one naturally occurring.

The term “variant” as used herein with respect to a peptide, refers toamino acid sequence variants that may have amino acids replaced,deleted, or inserted as compared to the wild-type polypeptide. Variantsmay be truncations of the wild-type peptide. A “deletion” is the removalof one or more amino acids from within the wild-type protein, while a“truncation” is the removal of one or more amino acids from one or moreends of the wild-type protein. Thus, a variant peptide may be made bymanipulation of genes encoding the polypeptide. A variant may be made byaltering the basic composition or characteristics of the polypeptide,but not at least some of its fundamental pharmacologic activities. Forexample, a “variant” of the Pseudomonas aeruginosa transit peptide maybe a mutated Pseudomonas aeruginosa transit peptide that retains itsability to enter cancer cells. In some cases, a variant peptide issynthesized with non-natural amino acids, such asε-(3,5-dinitrobenzoyl)-Lys residues. (Ghadiri & Femholz, J. Am. Chem.Soc., 112:9633-9635 (1990)). In some embodiments, the variant has notmore than 20, 19, 18, 17 or 16 amino acids replaced, deleted or insertedcompared to wild-type peptide or a portion thereof. In some embodiments,the variant has not more than 15, 14, 13, 12 or 11 amino acids replaced,deleted or inserted compared to wild-type peptide or a portion thereof.In some embodiments, the variant has not more than 10, 9, 8 or 7 aminoacids replaced, deleted or inserted compared to wild-type peptide or aportion thereof, in some embodiments, the variant has not more than 6amino acids replaced, deleted or inserted compared to wild-type peptideor a portion thereof. In some embodiments, the variant has not more than5 or 4 amino acids replaced, deleted or inserted compared to wild-typepeptide or a portion thereof. In some embodiments, the variant has notmore than 3, 2 or 1 amino acids replaced, deleted or inserted comparedto wild-type peptide or a portion thereof.

The term “amino acid,” as used herein, means an amino acid moiety thatcomprises any naturally-occurring or non-naturally occurring orsynthetic amino acid residue, i.e., any moiety comprising at least onecarboxyl and at least one amino residue directly linked by one, two,three or more carbon atoms, typically one (a) carbon atom. An amino acidmay be an L-isomer or a D-isomer of an amino acid.

The term “modified residue” as used herein refers to an amino acid thathas been modified using a method or technique which may include, but isnot limited to, one or more of the methods and techniques disclosedherein.

The term “derivative” as used herein with respect to a peptide refers toa peptide that is derived from the subject peptide. A derivationincludes chemical modifications of the peptide such that the peptidestill retains some of its fundamental pharmacologic activities. Forexample, a “derivative” of a Pseudomonas aeruginosa transport peptidecan be a chemically modified Pseudomonas aeruginosa transport peptidethat retains its ability to enter cancer cells. Chemical modificationsof interest include, but are not limited to, amidation, acetylation,sulfation, polyethylene glycol (PEG) modification, phosphorylation orglycosylation of the peptide. In addition, a derivative peptide maybe afusion of a polypeptide to a chemical compound, such as, but not limitedto, another peptide, drug molecule or other therapeutic orpharmaceutical agent or a detectable probe.

The term “percent (%) amino acid sequence identity” is defined as thepercentage of amino acid residues in a polypeptide that are identicalwith amino acid residues in a candidate sequence when the two sequencesare aligned. To determine % amino acid identity, sequences are alignedand if necessary, gaps are introduced to achieve the maximum % sequenceidentity; conservative substitutions are not considered as part of thesequence identity. Amino acid sequence alignment procedures to determinepercent identity are well known to those of skill in the art. Oftenpublicly available computer software such as BLAST, BLAST2, ALIGN2 orMegalign (DNASTAR) software is used to align peptide sequences. In aspecific embodiment, Blastp (available from the National Center forBiotechnology Information. Bethesda Md.) is used using the defaultparameters of long complexity filter, expect 10, word size 3, existence11 and extension 1.

When amino acid sequences are aligned, the % amino acid sequenceidentity of a given amino acid sequence A to, with, or against a givenamino acid sequence B (which can alternatively be phrased as a givenamino acid sequence A that has or comprises a certain % amino acidsequence identity to, with, or against a given amino acid sequence 8)can be calculated as:

% amino acid sequence identity=X/Y*100

-   -   where    -   X is the number of amino acid residues scored as identical        matches by the sequence alignment program's or algorithm's        alignment of A and B and Y is the total number of amino acid        residues in B.

If the length of amino acid sequence A is not equal to the length ofamino acid sequence B, the % amino acid sequence identity of A to B willnot equal the % amino acid sequence identity of B to A. When comparinglonger sequences to shorter sequences, the shorter sequence will be the“B” sequence. For example, when comparing truncated peptides to feecorresponding wild-type polypeptide, the truncated peptide will be the“B” sequence.

General

The present invention relates to cupredoxin derived peptides thatmaintain one or more pharmacologic activities of the cupredoxin andwhich may have improved pharmacokinetic properties, such as improvedstability, specific activity, half-life in the bloodstream, and/ordecreased immunogenicity, among others. Additionally, the presentinvention relates to compounds derived from the modified cupredoxinderived peptides, which in turn also maintain one or more pharmacologicactivities of the cupredoxin and which have improved pharmacokineticproperties. Finally, the invention relates to methods to use themodified cupredoxin derived peptides and compound made from them totreat and/or diagnose various conditions suffered by mammalian patients,and to research various conditions suffered by mammalian patients. TheSequence Listing submitted herewith is incorporated by reference in itsentirety herein.

Compositions

The invention relates to peptides that are modifications of cupredoxinderived peptides. In some embodiments the modified peptides haveimproved pharmacokinetic properties. In some embodiments, these modifiedcupredoxin derived peptides retain at, least one pharmacologic activityof the cupredoxin. In some embodiments, the modified cupredoxin derivedpeptides are isolated, substantially pure, or pharmaceutical grade. Inspecific embodiments, the modified cupredoxin derived peptides areintravenous pharmaceutical grade.

Cupredoxins, and specifically azurin from Pseudomonas aeruginosa, axeknown to have several useful pharmacologic activities that are usefulfor treating and/or diagnosing mammalian patients, and for conductingresearch on conditions suffered by mammalian patients. For example, manycupredoxin proteins, such as Pseudomonas aeruginosa azurin, have theability to specifically enter and kill many types of mammalian cancercells. Yamada et al., Cell Biol. 7:1418-1431 (2005); Hiraoka et al.,PNAS 101:6427-6432 (2004); Hiraoka et al., Biochem. Biophys. Res. Comm.338:1284-1290 (2005); U.S. patent application Ser. No. 11/244,105, filedOct. 6, 2005; U.S. patent application Ser. No. 10/720,603, filed Nov.24, 2003; U.S. patent application Ser. No. 10/047,710, filed Jan. 15,2002; U.S. patent application Ser. No. 11/485,252, filed Jul. 13, 2006,all of which are expressly incorporated herein by reference in theirentirety. Azurin from P. aeruginosa is also known to inhibit the growthof viral or bacterial infection, and more specifically HIV-1 infectionin peripheral blood mononuclear cells and also to inhibit parasitemia ofmalaria-infected mammalian red blood cells. Chaudhari et al., CellCycle. 5:1642-1648 (2006); U.S. patent application Ser. No. 11/436,591,filed May 19, 2006; U.S. patent application Ser. No. 11/436,590, filedMay 19, 2006, both of which are expressly incorporated herein byreference in their entirety. Azurin from P. aeruginosa is also known tointerfere with the ephrin signaling system in various mammalian cellsand tissues. U.S. patent application Ser. No. 11/436,592, filed May 19,2006, which is expressly incorporated herein by reference in itsentirety. Further, peptides derived from P. aeruginosa azurin are knownto inhibit angiogenesis in mammalian cells, and specifically humanumbilical vascular endothelium cells (HUVECs). U.S. patent applicationSer. No. 11/488,693, filed Jul. 19, 2006, which is expresslyincorporated herein by reference in its entirety. In some embodiments,the modified cupredoxin derived peptides of the invention retain atleast one pharmacologic activity of the cupredoxin from which they arederived. The pharmacologic activity of cupredoxin may be any usefulactivity of a cupredoxin. Pharmacologic activities of particularinterest include, but are not limited to, the ability to specificallyenter mammalian cancer cells, the inability to enter non-cancerousmammalian cells, the ability to enter pre-malignant mammalian cells, theability 10 kill mammalian cancer cells, the ability to killpre-malignant mammalian cells, the ability to inhibit the growth ofviral or bacterial infection, the ability to inhibit the HIV-1 infectionin peripheral blood mononuclear cells, the ability to inhibitparasitemia by malaria in malaria-infected red blood cells, and theability to inhibit angiogenesis in mammalian cells, and specificallyHUVECs. Methods to measure the amount of pharmacologic activity of thepeptide are provided in the above referenced applications andpublications.

Azurin, a cupredoxin from Pseudomonas aeruginosa utilizes a proteintransduction domain (PTD) to selectively enter human cancer cells. Theminimal motif PTD used by these cupredoxins had not been previouslyidentified. The mechanisms of entry by azurin, p18 (SEQ ID 14) and p28(SEQ ID 13) are detailed here and in the examples provided below.Generally, PTDs cluster into two groups based on their structuralcharacteristics, cationic residues or amphipathic α-helix, althoughseveral fall into both classes. In general, cationic peptides initiallyinteract with the cell membranes of prokaryotic and eukaryotic speciesby binding to negatively charged surface glycoproteins, facilitatingefficient entry into a broad range of normal and malignant cell lines.Kondejewski, L. H., et al., J Biol Chem 277: 67-74 (2002); Fuchs, S. M.and Raines, R. T., Biochemistry, 43: 2438-2444 (2004). The binding ofcationic peptides to HS is consistent with their high affinity for HS(Kd-109 nM), a value well in excess of that reported for azurin, p18(SEQ ID 14) and p28 (SEQ ID 13). Tran, D. et al, Proc Natl Acad Sci USA84; 7957-7961 (1987).

However, the cytotoxic effects exerted by synthetic, cationic,amphipathic α-helical diastereomeric peptides are not generally specificto cancer cells. Amphipathic cell penetrating peptides (CPPs) that arecytolytic to cancer cells either disrupt the cancer cell membrane, altermitochondrial permeability, or act through a specific receptor mediatedmechanism. Leuschner, C. and Hansel, W., Curr Pharm Des, 10: 2299-2310(2004). Synthetic magainins, a linear, helical, channel-forming orionophore class of peptides including those exclusively comprised ofLys, Ala, and Leu residues rapidly and irreversibly lyse hematopoieticand solid tumor target cells at doses below those cytotoxic to normalcells, but do not have the property of preferentially penetrating cancercells. Javapour, M. M., et al., J Med Chem, 39: 3107-3113 (1996);Cruciani, R. A., et al., Proc Natl Acad Sci USA 88: 3792-3796 (1991);Papo, N. and Shai, Y., Biochemistry, 42; 9346-9354 (2003). Peptidesgenerated through phage-display technology, though rather specific forlymphatic and tumor blood vessels, also do not induce cytotoxicity bydirect penetration of cancer cells.

In contrast, azurin and the two peptides derived from it (p28, SEQ. ID13, and p18, SEQ. ID 14) possess the unique property of preferentiallyentering cancer cells and inhibiting their proliferation throughcytostatic and cytotoxic mechanisms. It has been shown by confocalmicroscopy and FACS that p18 (SEQ. ID 14) is the minimal motifresponsible for azurin's preferential entry into human cancer cells.

In addition to entering cancer cells, p18 (SEQ ID NO: 14) and p28 (SEQID NO: 1.3) are able to enter tumors and mammalian organs, as is shownin FIGS. 14 through 49, which were obtained using the methods disclosedin Example 9. Surprisingly, p18 (SEQ ID NO: 14) and p28 (SEQ ID NO: 13)are also able to penetrate the blood-brain barrier and enter mammalianbrains, as demonstrated by, for example, FIGS. 16A, 16B, 17B, 19, 20,24, 26, 27A, 28B, 29, 30B, 31A-B, 33A-C, 34A-C, 36A, 38A, 39A, 41A-D,42, 43B, 44A-B, and 46.

Redox proteins, such as azurin, are not normally classified as CPPs, orantiproliferative agents. The amphipathic, azurin fragments p18 (SEQ IDNO: 14) and p28 (SEQ ID NO: 13) contain the 54-67 amino acid α-helicalstructure of azurin as well as a partial β-sheet structure and describea minimal sequence for cancer cell entry and cell cycle inhibitoryactivity, respectively. The entry of azurin, p28 (SEQ ID NO: 13), andp18 (SEQ ID NO: 14) is distinct from that of canonic CPPs. AberrantN-glycosylation on several cell surface receptors, including integrinsand cadherins, is associated with changes in progression and metastasisof cancers of diverse histogenesis, suggesting a role for as yet unknownN-glycosylated cell surface protein(s) in the initial steps of azurin,p18 (SEQ ID NO; 14) and p28 (SEQ ID NO: 13) penetration. Partridge, E.A., et al. Science 306: 120-124 (2004); Seales, E. C., et al., CancerRes 65:4645-4652 (2005).

The temperature dependent entry of cationic CPPs, which supports anendocytotic component to cell penetration, is reflected in the entry ofazurin and amino acid fragment 50-77 (p28 SEQ. ID 13). Yamada, T., etal., Cell Microbiol 7: 1418-1431 (2005). The entry of amino acids 50-67of azurin (p18 SEQ. ID 14) into normal and malignant cells appearsaccelerated relative to p28 (SEQ ID NO: 13). The lower K_(m) and higherV_(max) of p18 (SEQ ID NO: 14) suggest that amino acids 50-67 define anamphipathic structure when associated with phospholipid membranes thatmore closely represents the actual PTD of azurin. However, an energydependent endocytotic or pore related process does not appear to be theonly entry mechanism available to these peptides. For example, themetabolic and membrane potential inhibitors sodium azide and ouabain(Na+ K+ ATPase inhibitor), which inhibit the entry-of cationic peptides,did not impair the entry of either p18 (SEQ ID NO: 14) or p28 (SEQ IDNO: 13) into UISO-Mel-2 cells or fibroblasts (FIG. 10 B,C), suggestingthat either peptide may penetrate the cell membrane directly.

p18 (SEQ ID NO: 14), p28 (SEQ ID NO: 13) and azurin penetrate the plasmamembrane and reach late endosomes, lysosomes and the golgi associatedwith caveolae in what is thought to be a dynamin-independent clathrinindependent carrier mediated manner. Kirkham, M and Parton, R. G., BiochemBiophys Acta 1746; 349-363 (2005). Nocodazole, which disrupts caveolaetransport and caveolae-mediated endocytosis inhibited penetration by50-65%. The striking inhibition of penetration by nocodazole andrelative lack of inhibition by cytochalasin-D, which disrupts actinfilaments, supports caveolae mediated entry. Notably, the lack of effectof staurosporine demonstrates that dynamin does not play a large role inthe penetration of either peptide, Id. This route of entry has beendescribed for integral cell surface components and seemingly disparatemolecules, i.e., dextran, and a broad range of pathogens or theirproducts that also utilize caveolae to bypass classic endocytoticpathways. Depiction of cholesterol from the plasma membrane withβ-methylcyclodextran, filipin or nystatin to disrupt lipid rafts, plasmamembrane domains that provide fluid platforms to segregate membranecomponents and compartmentalize membranes. Significantly inhibited thepenetration of p18 (SEQ ID NO: 14) (50%) and p28 (SEQ ID NO: 13) (˜60%)into UISO-Mel-2 cells and fibroblasts (35% and 42%, respectively)demonstrating that a significant percentage (60%) of p18 (SEQ ID NO: 14)and p28 (SEQ ID NO: 13) penetrates the plasma membrane via caveolae.Caveolae are a 50- to 100-nm omega-shaped subset of lipid raftinvaginations of the plasma membrane defined by the presence of caveolinspecific proteins (caveolin-1, -2, or -3) that function as regulators ofsignal transduction.

Brefeldin A disrupts the Golgi apparatus and inhibited p18 (SEQ ID NO:14) accumulation, so it follows that this pathway is also utilized inp18 (SEQ ID NO: 14) and p28 (SEQ ID NO: 13) entry and intracellulartransport. Cell penetration of p18 (SEQ ID NO: 14) and p28 (SEQ ID NO:13) via caveolae comports with the evidence that inhibitors ofN-glycosylation reduce cell entry by 00% in UISO-Mel-2 cells and 25% and35% respectively in fibroblasts. The percentile differences between p18(SEQ ID NO: 14) and p28 (SEQ ID NO: 13) entry relate to the numbers ofN-glycosylation membrane structures in cancer vs. normal cells and therelative route of entry of p28 (SEQ ID NO: 13) and p18 (SEQ ID NO: 14)via this mechanism.

Azurin, p28 (SEQ ID NO; 13), and p18 (SEQ ID NO: 14) all bind to cancercells with high affinity and high capacity relative to many otherpotential anti-cancer peptides. After binding, this protein/receptorcomplex localizes in caveolae and is internalized, eventually moving(via caveosomes) to the golgi, ER, and nucleus. In addition tocaveolar-mediated entry, kinetic analysis also demonstrates that p28(SEQ ID NO: 13) and p18 (SEQ ID NO: 14) penetrate the plasma membranevia a non-clathrin caveolae mediated process. A clathrin- andcaveolin-independent pathway can exist as a constitutive internalizationmechanism, such as for the interleukin 2 receptor and for certainglycosyl-phosphatidylinositol (GPI)-anchored proteins. Lamaze, C., etal., Mol Cell 7: 661-671 (2001); Sabharanjak, S., et al., Dev Cell, 2:411-423 (2002). Clathrin- and caveolin-independent endocytosis is alsoused by pathogens to invade cells, either exclusively, as for the murinepolyoma virus, or in combination with a conventional pathway, as is thecase for the influenza virus. Ewers, H., et al, Proc Natl Acad Sci USA102: 15110-15115 (2005); Sieczkarski, S. B. and Whittaker, G. R., JVirol, 76: 10455-10464 (2002). An increase in caveolin-1 expression incancer cells over normal cells is not likely to be the sole basis forthe preferential entry of azurin, p28 (SEQ ID NO: 13) and p18 (SEQ IDNO: 14) into cancer cells. Fibroblasts and a number of other normalcells also have significant numbers of caveolae on their surface.

p18 (amino acids 50-67 of azurin, SEQ. ID 14) and p28 (amino acids 50-77of azurin. SEQ. ID 13) are not bound by cell membrane glycosaminoglycansand preferentially penetrate cancer cells via endocytotic, caveosomedirected and caveosome independent pathways. The cellular penetration ofp18 (SEQ ID NO: 14) and p28 (SEQ ID NO: 13) is unique relative to altcurrent CPPs in its preference for cancer cells. Surprisingly, theC-terminal 10-12 amino acids of p28 (SEQ ID NO: 13) are demonstrated tocomprise the domain responsible for cell cycle inhibition and apoptoticactivity/cytotoxicity. Furthermore, this same domain is most likely tocontact specific residues on a cell membrane and thus facilitate entry;amino acids 69, 70, 75, 76, and 85 of azurin in particular providecontact to the cell membrane. Once internalized, p28 (SEQ ID NO: 13)inhibits cancer cell proliferation initially through a cytostaticmechanism. Thus, it is now known that p18 (SEQ ID NO: 14) and p28 (SEQID NO: 13) account for the preferential entry of azurin into humancancer cells and a significant amount of the anti-proliferative activityof azurin on human cancer cells, respectively.

The cupredoxin derived peptides may be any cupredoxin, or variant,derivative or structural equivalent of cupredoxin, or a truncationthereof. In some embodiments, the cupredoxin derived peptide retains atleast one pharmacologic activity of the cupredoxin. In some embodiments,the cupredoxin may be, but is not limited to, azurin, plastocyanin,rusticyanin, pseudoazurin, auracyanin or azurin-like protein. Thecupredoxin derived peptides may be from any organism, including but notlimited to Pseudomonas aeruginosa, Phormidium laminosum, Thiobacillusferrooxidans, Achromobacter cycloclastes, Pseudomonas syringa, Neisseriameningitidis, Vibrio parahaemolyticus, Bordetella bronchiseptica,Bordetella pertussis, Chloroflexus aurantiacus and Neisseriagonorrhoeae. In some embodiments, the cupredoxin may be azurin,specifically from an organism including but not limited to Pseudomonasaeruginosa, Pseudomonas syringae Neisseria gonorrhaeae, Vibrioparahaemolyticus, or Bordetella bronchiseptica.

The cupredoxin derived peptides may be any variant, derivative orstructural equivalent of a cupredoxin. In some embodiments, thecupredoxin derived peptides may be a truncation of a cupredoxin. Thecupredoxin derived peptides may also be any cupredoxin peptide that isknown in the art and/or described in previous applications, such as U.S.patent application Ser. No. 11/244,105, filed Oct. 6, 2005; U.S. patentapplication Ser. No. 10/720,603, filed Nov. 24, 2003; U.S. patentapplication Ser. No. 10/047,710, filed Jan. 15, 2002, now U.S. Pat. No.7,084,105; U.S. patent application Ser. No. 11/485,252, filed Jul. 13,2006; U.S. patent application Ser. No. 11/436,591, filed May 19, 2006;U.S. patent application Ser. No. 11/436,590, filed May 19, 2006; U.S.patent application Ser. No. 11/436,592, filed May 19, 2006; and U.S.patent application Ser. No. 11/488,693, filed Jul. 19, 2006. All ofthese applications are expressly incorporated by reference herein intheir entirety. In some embodiments, the peptide is isolated. In someembodiments, the peptide is substantially pure or pharmaceutical grade.In other embodiments, the peptide is in a composition that comprises, orconsists essentially of, the peptide. In another specific embodiment,the peptide does not raise an immune response in a mammal, and morespecifically a human.

The cupredoxin derived peptides may be amino acid sequence variantswhich have amino acids replaced, deleted, or inserted as compared to thewild-type cupredoxin. These variants may be truncations of the wild-typecupredoxin. In some embodiments, amino acids may be replaced withunnatural or modified amino acids. An unnatural amino acid is one otherthan the 20 common amino acids. The cupredoxin derived peptides comprisea region of a cupredoxin that is less that the full length wild-typepolypeptide. In some embodiments, the cupredoxin derived peptidescomprise more than about 10 residues, more than about 15 residues ormore than about 20 residues of a truncated cupredoxin. In someembodiments, the cupredoxin derived peptides comprise not more thanabout 100 residues, not more than about 50 residues, not more than about40 residues, not more than about 30 residues or not more than about 20residues of a truncated cupredoxin. In some embodiments, a cupredoxinhas to the cupredoxin derived peptide, and more specifically SEQ ID NOS:1-12 at least about 70% amino acid sequence identity, at least about 80%amino acid sequence identity, at least about 90% amino acid sequenceidentity, at least about 95% amino acid sequence identity or at leastabout 99% amino acid sequence identity.

In specific embodiments, the cupredoxin derived peptide comprises P.aeruginosa azurin residues 50-77 (SEQ ID NO: 13), azurin residues 50-67(SEQ ID NO: 14), or azurin residues 36-89 (SEQ ID NO: 16). In otherembodiments, the variant of cupredoxin consists of P. aeruginosa azurinresidues 50-77 (SEQ ID NO: 13), azurin residues 50-67 (SEQ ID NO: 14),or azurin residues 36-89 (SEQ ID NO: 16). In other specific embodiments,the variant consists of the equivalent residues of a cupredoxin otherthat azurin. To determine the equivalent residues of another cupredoxin,the subject cupredoxin amino acid sequence will be aligned to thePseudomonas aeruginosa azurin sequence using BLAST, BLAST2, ALIGN2 orMegalign (DNASTAR), the relevant residues located on the P. aeruginosaazurin amino acid sequence, and the equivalent residues found on thesubject cupredoxin sequence, and the equivalent peptide thus designed.

In one embodiment of the invention, the cupredoxin derived peptidecomprises at least amino acids 57 to 89 of auracyanin B of Chloroflexusaurantiacus (SEQ ID NO: 21). In another embodiment of the invention, thecupredoxin derived peptide comprises at least amino acids 51-77 ofPseudomonas syringae azurin (SEQ ID NO: 27). In another embodiment ofthe invention, the cupredoxin derived peptide comprises at least aminoacids 89-115 of Neisseria meningitidis Laz (SEQ ID NO: 23). In anotherembodiment of the invention, the cupredoxin derived peptide comprises atleast amino acids 52-78 of Vibrio parahaemolyticus azurin (SEQ ID NO:28). In another embodiment of the invention, the cupredoxin derivedpeptide comprises at least amino acids 51-77 of Bordetellabronchiseptica azurin (SEQ ID NO: 29).

The cupredoxin derived peptides also include peptides made withsynthetic amino acids that are not naturally occurring. For example,non-naturally occurring amino acids may be integrated into the variantpeptide to extend or optimize the half-life of the composition in thebloodstream. Such variants include, but are not limited to, D,L-peptides(diastereomer), (see, for example Futaki et al., J. Biol. Chem.276(8):5836-40 (2001); Papo et al., Cancer Res. 64(16):5779-86 (2004);Miller et al, Biochem. Pharmacol. 36(1):169-76, (1987); peptidescontaining unusual amino acids (see, for example Lee et al., J. Pept.Res. 63(2)69-84 (2004)), olefin-containing non-natural amino acidfollowed by hydrocarbon stapling (see, for example Schafmeister et al.,J. Am. Chem. Soc. 122:5891-5892 (2000); Walenski et al., Science305:1466-1470 (2004)), and peptides comprisingε-(3,5-dinitrobenzoyl)-Lys residues.

In other embodiments, the cupredoxin derived peptide is a derivative ofa cupredoxin. The derivatives of cupredoxin are chemical modificationsof the peptide such that the peptide still retains some of itsfundamental pharmacologic activities. For example, a “derivative” ofazurin can be a chemically modified azurin that retains its ability toinhibit the growth of mammalian cancer cells. Chemical modifications ofinterest include, but are not limited to, hydrocarbon stabling,amidation, acetylation, sulfation, polyethylene glycol (PEG)modification, phosphorylation and glycosylation of the peptide. Inaddition, a derivative peptide maybe a fusion of a cupredoxin, orvariant, derivative or structural equivalent thereof to a chemicalcompound, such as but not limited to, another peptide, drag molecule orother therapeutic or pharmaceutical agent or a detectable probe.Derivatives of interest include chemical modifications by winch thehalf-life in the bloodstream of the peptides and compositions of theinvention can be extended or optimized, such as by several methods wellknown to those in the art, including but not limited to, circularizedpeptides (see, for example Monk et al., BioDrugs 19(4):261-78, (2005);DeFreest et al., J. Pept. Res. 63(5):40919 (2004)), N- and C-terminalmodifications (see, for example Labrie et al., Clin. Invest. Med.13(5):275-8, (1990)), and olefin-containing non-natural amino acidfollowed by hydrocarbon stapling (see, for example Schafmeister et al.,J. Am. Chem. Soc. 122:5891-5892 (2000); Walenski et al., Science305:1466-1470 (2004)).

In another embodiment, the peptide is a structural equivalent of acupredoxin or a truncation of a cupredoxin. Examples of studies thatdetermine significant structural homology between cupredoxins and otherproteins include Toth et al. (Developmental Cell 1:82-92 (2001)).Specifically, significant structural homology between a cupredoxin andthe structural equivalent is determined by using the VAST algorithm.Gibrat et al., Curr Opin Struct Biol 6:377-385 (1996); Madej et al.,Proteins 23:356-3690 (1995). In specific embodiments, the VAST p valuefrom a structural comparison of a cupredoxin to the structuralequivalent is less than about 10⁻³, less than about 10⁻⁵, or less thanabout 10⁻⁷. In other embodiments, significant structural homologybetween a cupredoxin and the structural equivalent is determined byusing the DALI algorithm. Holm & Sander, J. Mol. Biol. 233:123-138(1993). In specific embodiments, the DALI Z score for a pairwisestructural comparison is at least about 3.5, at least about 7.0, or atleast about 10.0.

One specific cupredoxin derived peptide of interest is a fusion of theentry domain of cupredoxin with a cargo compound. In some embodiments,cupredoxin derived peptides may specifically enter into a mammaliancancer cell, and thus may be used to deliver a cargo compound into acell, and specifically into a cancer cell. A cupredoxin transportpeptide comprises a cupredoxin entry domain. The term “cupredoxin entrydomain” refers to a fragment of a cupredoxin that includes the aminosequence that is required for the entry of cupredoxin into a mammaliancancer cell. In specific embodiments, the cupredoxin transport peptideis SEQ ID NOS: 13-17, or equivalent residues from another cupredoxin.The present invention encompasses cupredoxin transport peptidescomplexed with cargo compounds that have been modified to improve theirpharmacokinetic properties. The cargo compound as well as the cupredoxintransport peptide may be modified by the methods described herein toimprove pharmacokinetic properties. These complexes can then be used inthe methods of the invention to deliver the cargo compound intomammalian cancer cells to treat patients suffering from cancer. Cargocompounds delivered by the materials and methods of the presentinvention include, but are not limited to, proteins, lipoproteins,polypeptides, peptides, polysaccharides, nucleic acids, includinganti-sense nucleic acids, dyes, fluorescent and radioactive lags,microparticles or nanoparticles, toxins, inorganic and organicmolecules, metals, small molecules, and drugs. In some embodiments, thedrugs and toxins kill tumor cells. Such cupredoxin transport peptidesand complexes made with them are provided in U.S. patent applicationSer. No. 11/244,105, filed Oct. 6, 2005, which is expressly incorporatedherein by reference in its entirety.

In some embodiments, the fusion between the cargo compound and thecupredoxin derived peptide may be by a linkage that is selectivelycleaved after entry of the fused peptide into the cell. In someembodiments, such a linkage improves the pharmacokinetic properties ofthe cupredoxin transport peptide-cargo compound complex. In someembodiments, the stability of the cupredoxin transport peptide-cargocompound complex in plasma is enhanced. In some embodiments, the linkagemay be one that is selectively cleaved in the lysosomes of a mammaliancell. In other embodiments, the linkage may be one that is cleaved bycathepsin B, a cysteine protease located in the lysosomes orextracellularly in proximity to cancerous or arthritic sites. In somesuch embodiments, the linkage is a Val-Cit linkage.

In another embodiment, the peptide is a cupredoxin, or variant,structural equivalent, or derivative thereof that is a conjugate ofPep42, a cyclic 13-mer oligopeptide, CTVALPGGYRVRVC (SEQ ID. NO: 3505)that specifically binds to glucose-regulated protein 78 (GRP78) and isinternalized into cancer cells. The cupredoxin or variant, structuralequivalent, or derivative of cupredoxin may be conjugated with Pep42(SEQ ID. NO: 3505) pursuant to the synthesis methods disclosed in Yonedaet al., “A cell-penetrating peptidic GRP78 ligand for tumorcell-specific prodrug therapy,” Bioorganic & Medicinal ChemistryInciters 18; 1632-1636 (2008), the disclosure of which is incorporatedin its entirety herein.

In some embodiments the cupredoxin derived peptide may be attached toPep42 (SEQ ID NO: 3505). In some embodiments, Pep42 (SEQ ID. NO: 3505)may be further fused with a drug. It is believed that Pep42 (SEQ ID. NO:3505) specifically binds to glucose regulated protein 78 (GRP78), whichis overexpressed in cancer cells, and is specifically present on thecancer cell surface. Yoneda, et al., Bioorganic & Medicinal ChemistryLetters 18 1632-1636 (2008). Pep42 (SEQ ID. NO: 3505) is efficientlyinternalized through the GRP78 receptor. Thus, in some embodiments, acupredoxin derived peptide-Pep42 fusion peptide may have enhancedspecificity to cancer cells. In some such embodiments, the fusionbetween Pep42 (SEQ ID. NO: 3505) and the cupredoxin derived protein maybe through a Val-Cit linkage, a cathepsin B. In some embodiments, thePep42-drug conjugate may be via a Val-Cit linkage. Pep42-drug conjugatescontaining cathepsin B-cleavable linkers are likely to be stable in theplasma and selectively release their drug specifically in the targetedtissue. In some embodiments of the invention, Pep42 (SEQ ID. NO: 3505)is linked to p-aminobenzylalcohol via an amidic bond, which is thenattached to the drag or cupredoxin derived peptide via a carbonate orcarbamate Functionality. In such embodiments, the enzymatic cleavagewithin the cancer cell delivers an unmodified cupredoxin derived proteinor drug inside the cell-.

In some embodiments, the cupredoxin-derived peptide is conjugated with ananoparticle, for example a noble metal such as gold or platinum, tocreate a hybrid system that can be used in therapeutic applications,diagnostics, and imaging.

In some embodiments, amino acids residues in the cupredoxin derivedpeptides that are conserved among cupredoxins with the desiredpharmacologic activity are conserved in modified cupredoxin derivedpeptides with improved pharmacokinetic properties. For example, it isknown that within the cupredoxin entry domain of Pseudomonas aeruginosaazurin, several residues are conserved among azurins and azurin-likeproteins from several species, Pseudomonas aeruginosa, Pseudomonassyringae, Neisseria gonorrhaeae, Vibrio parahaemolyticus, and Bordetellabronchiseptica. Yamada et al. Cell. Microbiol. 7:1418-1431 (2005). Insome embodiments, the cupredoxin derived peptide retains one or moreamino acid residues corresponding to residues 62, 63, 69, 72, 74 and 77P. aeruginosa azurin (SEQ ID NO: 1). In another embodiment, thecupredoxin peptide comprises a conserved amino acid sequenceDGXXXXXDXXYXKXXD (SEQ ID NO: 46) or DGXXXXDXXYXKXXD (SEQ ID NO: 47)where D is aspartic acid, G is glycine, Y is tyrosine, K is lysine and Xis any amino acid.

Modifications

The present invention relates to modifications of cupredoxin derivedpeptides that are variants or derivatives or truncations, and inspecific embodiments, maintain one or more pharmacologic activities,and/or that improve the pharmacokinetic properties of the peptide. Thesemodifications include, but are not limited to, variants and derivativesof the peptides that may increase their stability, specific activity,plasma half life, and/or decrease immunogenicity of the cupredoxinderived peptide, while retaining the ability of the cupredoxin to entermammal cancer cells and/or inhibit the growth of mammalian cancer cells.Such variants include, but are not limited to, those which decrease thehydrolyses of the peptide decrease the deamidation of the peptide,decrease the oxidation, decrease the immunogenicity and/or increase thestructural stability of the peptide. It is contemplated that two or moreof the modifications described herein may be combined in one modifiedcupredoxin derived peptide, as well as combinations of one or moremodifications described herein with other modification to improvepharmacokinetic properties that are well know to those in the art. Manymethods to design such variants and derivatives are well know in theart.

One method of chemically modifying a cupredoxin or cytochrome c551 orvariant, derivative, truncation, or structural equivalent thereof may beto follow the steps taken to design an anti-HIV small protein, CCL-5(RANTES) with improved pharmaceutical properties by, for example,hydrophobic N-terminal modification, total protein-polymer conjugatechemicals synthesis, coded and noncoded amino acid mutagenesis, peptidebackbone engineering, and site-specific polymer attachment. Anti-HIVproteins can be designed by incorporating natural and unnatural aminoacid residues into CCL-5 analogues bearing polymer substituents atvarying attachment positions. Studies indicate that in vitro anti-HIVactivity of polymer-modified CCL-5 derivatives correlates with CCR-5signaling, so changes to the peptide should not disrupt CCR-5 activity.See Miranda, et al., J. Am. Chem. Soc. 129: 13153-13159 (2007), thedisclosure of which is incorporated in its entirety herein.

Biotransformation

One approach to improving the pharmacokinetic properties of the peptidesis to create variants and derivatives of the cupredoxin derived peptidesthat are less susceptible to biotransformation. Biotransformation mydecrease the pharmacologic activity of the peptide as well as increasethe rate at which it is eliminated from the patient's body. One way ofachieving this is to determine the amino acids and/or amino acidsequences that are most likely to be biotransformed and to replace theseamino acids with ones that are not susceptible to that particulartransformative process.

In some embodiments, the cupredoxin derived peptides may includeunnatural amino acids or modified amino acids. In some embodiments, theintroduction of certain unnatural amino acids enhances thepharmacokinetic properties of the cupredoxin derived peptide. Suchintroduction may be site-specific and may be done to avoid certainbiochemical modifications in vivo. Exemplary unnatural amino acidsinclude β-amino acids (e.g., b3 and b2), homo-amino acids, cyclic aminoacids, aromatic amino acids, Pro and Pyr derivatives, 3-substitutedAlanine derivatives, Glycine derivatives. Ring-substituted Phe and TyrDerivatives, α,α disubstituted amino acids. Linear Core Amino Acids andDiamine Acids. Such unnatural amino acids may be incorporated intopeptides by site directed modification, ribosomal translation, or bychemical synthesis of the peptide. Each of these methods may be appliedin synthesizing cupredoxin derived peptides.

For example, modified cupredoxin derived peptides may be synthesized bythe use of wild-type Aminoacyl-tRNA synthetases (AARSs) with unnaturalamino acids building for the production of unnatural cupredoxinvariants. See Hartman, et al., PLoS One, 2(10): e972 (2007); Miranda, etat, J. Am. Chem. Soc. 129: 13153-13159 (2007). The specificity of theribosomal translation apparatus limits the diversity of unnatural aminoacids that may be incorporated into peptides using ribosomaltranslation. Over ninety unnatural building blocks that are AARSsubstrates have been uncovered including side chain and backboneanalogs. Hartman, et al., PLoS One, 2(10): e972 (2007). Over fiftyunnatural amino acids may be incorporated into peptides with highefficiency using an all-enzymatic translation system, with peptidescontaining up to thirteen different unnatural amino acids. Hartman, etal., PLoS One, 2(10): e972 (2007). Unnatural amino acids include, butare not limited to, 4-fluoro-glutamates, 4-methyl analogs, L-threo-βaspartic acid, S-2-aminoethyl cysteine, trans-dehydro lysine,aza-leucine, L-canavanine, L-NG-methyl arginine, N^(G) hydroxy arginine,vinyl-L-NIO, DL-β-hydroxy norvaline, L-Glu γ-methyl ester, L-Aspβ-methyl ester, L-glutamic acid y-hydrazide, L-albizziine, L-theanine,β-2-thiazolyl-alanine, β-(1,2,4-triazol-3-yl-alanine), 3-fluorotyrosine, 3-fluoro valine, 3-nitro tyrosine, 2-fluoro Phe, 2-thienylAla, β-methyl Phe, β-thienyl Ser, p-nitrophenylalanine,3-(thianaphthen-3-yl)-L-alanine, L-quisqualic acid, ibotenic acid,DL-α-(2-thienyl)glycine, L-phenylglycine, 2-amino hex-5-ynoic acid,crotylglycine, L-norleucine, L-norvaline, L-ethionine,L-β-azidohomoalanine, 6,6,6,-trifluoronorleucine,2-amino-4,4,4-trifluorobutyric acid, L-C-propargyl glycine, L-allylglycine, β-Cyclopropyl alanine, photo-Met, 3-fluoro-valine,t-butyl-glycine, G-methyl-L-threonine, (2S,3S)-2-amino-3-methoxybutanoicacid, 4-thia-isoleucine, L-cyclohexyl glycine, 5′,5′,5′-trifluoroleucine, β-t-butyl-alanine, β-cyclopentyl alanine, photo-Leu,thiazolidine-2-carboxylic acid, thiazolidine-4-carboxylic acid,3,4-dehydro proline, L-azetidine-2-carboxylic acid, 1-aminocyclopentanoic acid, 1-aminocyclohexanoic acid, β-hydroxy acids,N-methyl His, N methyl Asp, α-hydroxy acids, and α-hydroxy methionine.The Hartmann and Miranda references, and all unnatural building blocksand amino acids described and disclosed by these references, are herebyincorporated by reference in their entirety herein. In some embodiments,such amino acids may be incorporated in cupredoxin derived peptides.

Other modifications may include the use of optically active α-aminoacids. The use of optically active α-amino acids and their derivativesis being expanded for their use in pharmaceuticals, agrochemicals and aschiral ligands. In particular, chiral glycine and alanine equivalentsplan an important role. At least one stereoselective strategy forconstructing amino acids has been proposed, allowing for enantiopureα-amino acids in predetermined stereochemistry. Lu, et al. “AsymmetricSynthesis of α-amino acids; Preparation and alkylation of monocycliciminolactones derived from α-Methyl trans-cinnamaldehyde” published onInternet on Sep. 11, 2008 (to be published in J. Org. Chem.). Themodified cupredoxin derived peptides may be synthesized using theoptically active α-amino acids to produce enantiomerically enrichediterations.

Hydrolysis is generally a problem in peptides containing aspartate.Aspartate is susceptible to dehydration to form a cyclic imideintermediate, causing the aspartate to be converted to the potentiallyinactive iso-aspartate analog, and ultimately cleaving the peptidechain. For example, in the presence of aspartic acid-proline in thepeptide sequence, the acid catalyzed formation of cyclic imideintermediate can result to cleavage of the peptide chain. Similarly, inthe presence of aspartic acid-glycine in the peptide sequence, thecyclic intermediate can be hydrolyzed either into the original aspartateform (harmless) or into the iso-aspartate analog. Eventually, all of theaspartate form can be completely converted into the iso-aspartateanalog. Similarly sequences with serine can also be dehydrated to form acyclic imide intermediate that can cleave the peptide chain. Cleavage ofthe peptide may result in reduced plasma half-life as well as reducedspecific pharmacologic activity of the peptide.

It is contemplated that substituting other amino acids for asparagineand/or serine in the sequence of the cupredoxin derived peptide mayresult in a peptide with improved pharmacokinetic properties such as alonger plasma half-life and increased specific activity of apharmacologic activity of the peptide. In one contemplated variant, atone or more asparagine residues of the cupredoxin derived peptide may bereplaced with another amino acid residue, and specifically a glutamicacid residue. In another contemplated variant, one or more serineresidues of the cupredoxin derived peptide may be replaced with anotheramino acid residue, and specifically a threonine residue. In somevariants of cupredoxin derived peptide, one or more asparagine residuesand one or more serine residues are substituted. In some embodiments,conservative substitutions are made. In other embodiments,non-conservative substitutions are made.

Deamidation of amino acid residues is a particular problem inbiotransformation. This base-catalyzed reaction frequently occurs insequences containing asparagine-glycine or glutamine-glycine and followsa mechanism analogous to the aspartic acid-glycine sequence above. Thede-amidation of the asparagine-glycine sequence forms a cyclic imideintermediate that is subsequently hydrolyzed to form the aspartate oriso-aspartate analog of asparagine. In addition, the cyclic imideintermediate can lead to racemization into D-aspartic acid orD-iso-aspartic acid analogs of asparagine, all of which can potentiallylead to inactive forms of the peptide.

It is contemplated that deamidation in the cupredoxin peptides may beprevented by replacing a glycine, asparagine and/or glutamine of theasparagine-glycine or glutamine-glycine sequences of the cupredoxin withanother amino acid and may result in a peptide with improvedpharmacokinetic properties, such as a longer plasma half-life andincreased specific activity of a pharmacologic activity of the peptide.In some embodiments, the one or more glycine residues of the cupredoxinderived peptide are replaced by another amino acid residue. In specificembodiments, one or more glycine residues of the cupredoxin derivedpeptide are replaced with a threonine or an alanine residue, in someembodiments, the one or more asparagine or glutamine residues of thecupredoxin derived peptide are replaced by another amino acid residue.In specific embodiments, one or more asparagine or glutamine residues ofthe cupredoxin derived peptide are replaced with an alanine residue, inother specific embodiments, the glycine at residues 58 and/or 63 of P.aeruginosa azurin (SEQ ID NO: 1), or equivalent glycines of othercupredoxins, are replaced with an alanine or a threonine. In otherspecific embodiments, the methionine at residue 59 of P. aeruginosaazurin (SEQ ID NO: 1), or an equivalent methionine residue of anothercupredoxin derived peptide, is replaced by an alanine residue, in otherspecific embodiments, the glycine at residue 63 of P. aeruginosa azurin(SEQ ID NO: 1), or an equivalent glycine residue of another cupredoxinderived peptide, is replaced by an threonine residue. In someembodiments, conservative substitutions are made. In other embodiments,non-conservative substitutions are made. In specific embodiments, themodified cupredoxin derived peptide of the invention comprises thefollowing sequence, wherein the underlined amino acids are substitutedinto the wild type Pseudomonas aeruginosa azurin sequence:

(SEQ ID NO: 30) LSTAADMQAVVTDTMASGLDKDYLKPDD.

Reversible and irreversible oxidation of amino acids are otherbiotransformative processes that may also pose a problem that may reducethe pharmacologic activity, and/or plasma half-life of cupredoxinderived peptides. The cysteine and methionine residues are thepredominant residues that undergo reversible oxidation. Oxidation ofcysteine is accelerated at higher pH, where the thiol is more easilydeprotonated and readily forms ultra-chain or inter-chain disulfidebonds. These disulfide bonds can be readily reversed in vitro bytreatment with dithiothreitol (DTT) or tris(2-carboxyethylphosphine)hydrochloride (TCEP). Methionine oxidizes by both chemical andphotochemical pathways to form methionine sulfoxide and further intomethionine sulfone, both of which are almost impossible to reverse.

It is contemplated that oxidation in the cupredoxin derived peptides maybe prevented by replacing methionine and/or cysteine residues with otherresidues. In some embodiments, one or more methionine and/or cysteineresidues of the cupredoxin derived peptide are replaced by another aminoacid residue. In specific embodiments, the methionine residue isreplaced with a leucine or valine residue. In other specificembodiments, one or more of the methionines at residues 56 and 64 of P.aeruginosa azurin (SEQ ID NO: 1), or equivalent methionine residues inother cupredoxin derived peptides, are replaced with leucine or valine.In some embodiments, conservative substitutions are made. In otherembodiments, non-conservative substitutions are made. In specificembodiments, the cupredoxin peptides of the invention comprise one ofthe following sequences, wherein the underlined amino acid issubstituted into the wild type Pseudomonas aeruginosa azurin sequence:

(SEQ ID NO: 31) LSTAADLQAVVTDGLASGLDKDYLKPDD or (SEQ ID NO: 32)LSTAADVQAVVTDGVASGLDKDYLKPDD.

Another biotransformative process that may affect the pharmacologicactivity, plasma half-life and/or immunogenicity of the cupredoxinderived peptides is diketopiperazine and pyroglutamic acid formation.Diketopiperazine formation usually occurs when glycine is in the thirdposition from the N-terminus, and more especially if proline or glycineis in position 1 or 2. The reaction involves nucleophilic attack of theN-terminal nitrogen on the amide carbonyl between the second and thirdamino acid, which leads to the cleavage of the first two amino acids inthe form of a diketopiperazine. On the other hand, pyroglutamic acidformation may be almost inevitable if glutamine is in the N-terminus.This is an analogous reaction where the N-terminal nitrogen attacks theside chain carbonyl carbon of glutamine to form a deaminatedpyroglutamyl peptide analog. This conversion also occurs in peptidecontaining asparagine in the N-terminus, but to a much lesser extent.

It is contemplated that diketopiperazine and pyroglutamic acid formationmay be decreased in cupredoxin derived peptides by replacing glycine inposition 1, 2, or 3 from the N-terminus, proline in position 3 from theN-terminus, or asparagine at the N-terminus of the peptide with anotheramino acid residue. In some embodiments, a glycine in positions 1, 2, or3 from the N-terminus of the cupredoxin derived peptide is replaced withanother amino acid residue. In specific embodiments, the glycine residueis replaced by a threonine or alanine residue. In another embodiment, aproline at position 3 from the N-terminus of the cupredoxin derivedpeptide is replaced with another amino acid residue. In specificembodiments, the proline is replaced by an alanine residue. In anotherembodiment, an asparagine at the N-terminus is replaced with anotheramino acid residue. In specific embodiments, the asparagine residue isreplaced by a glutamine residue. In some embodiments, conservativesubstitutions are made. In other embodiments, non-conservativesubstitutions are made.

Another biotransformative process that may affect the pharmacologicactivity, plasma half-life and/or immunogenicity of the cupredoxinderived peptide is racemization. This term is loosely used to refer tothe overall loss of chiral integrity of the amino acid or peptide.Racemization involves the base-catalyzed conversion of one enantiomer(usually the L-form) of an amino acid into a 1:1 mixture of L- andD-enantiomers. One way to improve stability of the peptide in general isby making a retro-inverso (D-isomer) peptide. The double inversion ofpeptide structure often leaves the surface topology of the side-chainintact and has been used extensively to stabilize biologically activepeptides. Snyder et al., PLoS Biol, 2:0186-0193 (2004). A D-amino acidsubstituted Tat is internalized into cells as well as the L-amino acidpeptide. Futaki et at, J. Biol. Chem. 276:5836-5840 (2001); Huq et al.,Biochemistry 38:5172-517 (1999). In some embodiments, one or more aminoacid residues of the cupredoxin derived peptide are replaced by theD-isomer of that amino acid residue. In other embodiments, all of theamino acid residues of the cupredoxin derived peptide are replaced withD-isomers of those residues. In one embodiment, the modified cupredoxinderived peptide is a retro-inverso (D-isomer) version of the cupredoxinderived peptide. In a specific embodiment, the modified cupredoxinderived peptide is

DDPKLYDKDLGSAMGDTVVGQMDAATSL (SEQ ID NO: 45).

In other specific embodiments, the modified cupredoxin derived peptidesare retro-inverso versions of cupredoxin derived peptides, including SEQID NOS: 1777-3504.

Other methods to protect a cupredoxin derived peptide from biotransformative degradation are N-acetylation and C-amidation. Thesederivatives may protect the peptide from degradation and may make thecupredoxin derived peptide more closely mimic the charge state of thealpha amino and carboxyl groups in the native protein. Peptides with theN-acetylation and/or C-amidation can be provided by commercialsuppliers. In one embodiment of the invention, the N-terminus of thecupredoxin derived peptide may be acetylated. In another embodiment ofthe invention, the C-terminus of the cupredoxin derived peptides may beamidated. In one specific embodiment, the modified cupredoxin derivedpeptide is

Acetylation-LSTAADMQGVVTDGMASGLDKDYLKPDD-amidation (SEQ ID NO: 33).

Cyclization is an additional manner of biotransformation that may bebeneficial to therapeutic peptides including the cupredoxins asdescribed herein. Cyclization may stabilize therapeutic peptides,allowing them to be stored longer, be administered at lower doses and beadministered less frequently. Cyclization has been shown to protectpeptides against peptidase and protease degradation. Cyclization can bedone chemically or enzymatically. Enzymatic cyclization is generallyless problematic than chemical cyclization, as chemical cyclization canlack in regio- and stereospecifically, can lead to multimerization inlieu of cyclization and can require complicated multistep processes.Indeed, it has been shown that thioether cyclization is more protectiveand stable than a disulfide bond against proteolytic enzymes.

Enzymatic cyclization has been shown inantibiotics—(methyl)lanthionine-containing bacterial peptides. E.g., R.Rink, et al., “Lantibiotic Structures as Guidelines for the Design ofPeptides That Can Be Modified by Lantibiotic Enzymes” 44 Biochem.,8873-82 (2005); R. Rink, et al., “Production of DehydroaminoAcid-Containing Peptides by Lactococcus lactis” 73:6 Applied andEnvironmental Microbiology, 1792-96 (2007); R. Rink, et al., “NisC, theCylcase of the Lantibiotic Nisin, Can Catalyze Cyclization of DesignedNonlantibiotic Peptides” 46 Biochem., 13179-89 (2007) (each of which ishereby incorporated by reference in its entirety). Lantibiotics areproduced by and inhibit the growth of gram-positive bacteria. Inlantibiotics, dehydroalanine and dehydrobutyrine are created by enzymemediated dehydration of serine and threonine residues. Cysteines arethen enzymatically coupled to the dehydrated serine and threonineresidues to form thioether cyclizations. Naturally occurringlantibiotics show such couplings via thioether bonds between residuesthat are up to 19 residues apart. Thioether ring formation depends uponthe leader peptide. The location of the cyclization depends upon thecyclase mediated regio- and stereospecific ring closure and thepositions of the dehydratable serine and threonine residues.

The best characterized of the lantibiotics is nisin a pentacyclicpeptide antibiotic produced by Lactococcus lactis. Nisin is composed offour methyl lanthionines, one lanthionine, two dehydroalanines, onedehydrobutyrine, and twenty-six unmodified amino acids Nisin*s fivethioether cross-links are formed by the addition of cysteine residues todehydroalanine and dehydrobutyrine residues that originate from serineand threonine. Nisin contains thioether-containing amino acids that areposttranslationally introduced by a membrane-associated enzyme complex.This enzyme complex includes: transporter NisT, serine and threoninedehydratase NisB, and cyclase NisC, NisB dehydrates serine and threonineresidues, converting them into dehydroalanine and dehydrobutyrine,respectively. This is followed by NisC catalyzed enantioselectivecoupling of cysteines to the formed dehydroresidues. NisT facilitatesthe export of the modified prenisin. Another enzyme, NisP cleaves thenisin leader peptide from prenisin.

The cyclase NisC has been well characterized. Li et al, “Structure andMechanism of the Lantibiotic Cyclase Involved in Nisin Biosynthesis” 311Science, 1464-67 (2006) (hereby incorporated by reference in itsentirety).

An analysis of cyclization in lantibiotics has led to the identificationof amino acid sequences and characteristics in peptides that favorcyclization. It has been shown that the NisB enzyme dehydrates moreoften where certain amino acids flank the serine and threonine residues.It has been shown that cyclization occurs more often in lantibioticpropeptides where hydrophobic, nonaromatic residues are in proximity tothe serine and threonine residues. The flanking residues of the modifiedcysteines are typically less hydrophobic than the flanking residues ofthe modified threonines and serines. Exceptions have been found,including hexapeptides VSPPAR, YTPPAL and FSFKAK. The hexapeptidessuggest that the presence of a proline at position 3 or 4 or havingphenylalanine flanking both sides may prohibit dehydration. The ringsare typically formed by coupling a dehydrated residue to a C-terminallylocated cysteine. However, rings may be formed by coupling a dehydrateresidue to a N-terminally located cysteine.

It has also been shown that the nisin dehydrating and transport enzymesare not specific to nisin and may, in fact, be used to modify non-nisinpeptides (and non-lantibiotic peptides). NisB has been shown todehydrate serine and threonine residues in peptides such as humanpeptide hormones when such peptides are N-terminally fused to thelantibiotic leader peptide. On non-(antibiotic peptides, similar ringformation characteristics apply; namely, the extent of dehydration canbe controlled by the amino acid context of the flanking region of thedehydratable serine and threonine residues. The presence of hydrophobicflanking residues (e.g., alanine and valine) around the serines andthreonines allowed full dehydration and therefore enhanced thioetherring formation. The presence of an N-terminal aspartate and C-terminallyflanked arginine prevented dehydration. It also shown that the presenceof proline residues and phenylalanine residues is disfavorable fordehydration. Generally, the presence of hydrophilic flanking residuesprevented dehydration of the serine and threonine residues. Hydrophobicflanking favors dehydration; hydrophilic flanking disfavors dehydration.Studies have shown that where dehydration docs occur, the averagehydrophobicity of the flanking residues of serines and threonine ispositive—0.40 on the N-terminal side and 0.13 on the C-terminal side.Also, the average hydrophobicity of the residues flanking serines andthreonines that are not dehydrated is negative—−0.36 on the N-terminalside and −1.03 on the C-terminal side. Dehydration is not restricted bythe presence of a series of flanking threonine residues and is notrestricted by the distance between the nisin leader peptide and theresidue to be dehydrated.

NisC has been shown to catalyze the regiospecific formation of thioetherrings in peptides unrelated to naturally occurring lantibiotics.Generally, such peptides must be fused to the nisin leader peptide. Insome cases, thioether rings may form spontaneously, for example where adehydroalanine is spaced by two amino acids from a cysteine. Unlikespontaneous cyclization, NisC catalyzed cyclization is stereospecificfor dehydrated pre-nisin. Consequently, the methyllanthionines andlanthionine in nisin are in the DL configuration. It is thought thatcyclization in nonlantibiotic peptides will also be stereospecific.

These principles can be applied to the compounds described herein,including cupredoxins and variants and truncations thereof.

Thioether Bridges

In nature, lantibiotic-enzyme-induced thioether bridges occur with up to19 amino acids under the bridge. Thioether bridges with 2 to 4 aminoacids under the bridge are abundant.

In some embodiments, the cupredoxin may be modified by introducingthioether bridges into the structure. The azurin truncation p28 (SEQ IDNO: 13), for example, may be modified using this method. Extendedmolecular dynamics simulations (70 ns) using software package GROMACS(www.gromacs.org) suggest that, at 37° C., the region of the p28 (SEQID) NO: 13) alpha helix from position 6 to 16 is unstable, and that thepeptide tends to adopt a beta sheet conformation. (See FIGS. 4 (A) and(B)). This, together with the fact that the part of the moleculepresumed to be responsible for interaction with p53 remains solventexposed, suggests that introduction of a thioether bridge in this regionof the p28 (SEQ ID NO: 13) peptide may not affect its functionality.

The amino acid sequence of p28 is SEQ ID NO: 13(LSTAADMQGVVTDGMASGLIDKDYLKPDD). The amino acid sequence known as p18 isSEQ ID NO: 14 (LSTAADMQGVVTDGMASG). Within p28 (SEQ ID NO: 13), thesequence SGLDKD may interact with p53. Thioether bridges can be formedbetween Ser/Thr on me N-side to Cys on the C-side. The serine/threoninemay be dehydrated and subsequently coupled to the cysteine. Threoninesare preferred since they are more easily dehydrated than serines.Generally, hydrophobic flanking residues (at least one) to the threonineare preferred since they enhance the extent of dehydration. Negativelycharged amino acids, glutamate and aspartate, that are flanking residueshave a strong negative effect on dehydration. Generally, hydrophilicflanking residues, especially glycine, do not favor dehydration.Preceding the Cys there is a slight preference for charged hydrophilicresidues, especially glutamate/aspartate. Depending on the size of thethioether ring, the bulkiness of the amino acids that participate in thering matters.

In one embodiment, the truncated azurin sequence is SEQ ID NO. 3507,LSTAADMQGVVTDGMASGLDKDYLTPGC. A thioether bridge is formed betweenpositions 25 and 28, and will be fully protected againstcarboxyetidases. Positions 2, 3 and 25 will be dehydrated, but neitherthe import sequence, nor the sequence thought to be relevant forinteraction with p53, is altered by thioether ring introduction. Assuch, peptide activity should not be altered. The threonine is betweentwo hydrophobic amino acids and hence is expected to be folly dehydratedby dehydratase, NisB, according to specific guidelines. See Rink er al.,Biochemistry 2005. The same guidelines also predict cyclizationinvolving positions 25 and 28 by cyclase NisC, especially because of theaspartate located before the cysteine.

In another embodiment, the truncated azurin sequence isLSTAADCQGVVTDGMASGLDKDYLKPDD (SEQ ID NO. 3508) and the thioether bridgeis formed between positions 3 and 7. The ring between position 3 and 7mimics ring A of nisin and makes use of the existing threonine atposition 2. The aspartate at position 6 will favor cyclization.

In another embodiment, the truncated azurin sequence isLSTAACMQGVVTDGMASOLDKDYLKPDD, (SEQ ID NO. 3509) and the threonine inposition 2 is utilized to form a thioether bridge.

In another embodiment, two or more of the thioether rings in thetruncated azurins described in the paragraphs above are combined intoone peptide.

In another embodiment, many truncated azurin sequences can be createdand screened for threonine rings by analyzing the peptides with a ringof one lanthionine and two to three additional amino acids under thesulfur bridge. As examples, this might involve one or combinations ofthe sequences below, where the bolded mutations facilitate completemodification;

(SEQ ID NO: 3510) LSTACDMQGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 3511)LSTAATMQCVVTDGMASGLDKDYLKPDD (SEQ ID NO: 3512)LSTAATMQGCVTDGMASGLDKDYLKPDD (SEQ ID NO: 3513)LSTAANTQGVCTDGMASGLDKDYLKPDD (SEQ ID NO: 3514)LSTAANTQGVCTDGMASGLDKDYLKPDD (SEQ ID NO: 3515)LSTAADMTAVCTDGMASGLDKDYLKPDD (SEQ ID NO: 3516)LSTAADMTAVVCDGMASGLDKDYLKPDD (SEQ ID NO: 3517)LSTAADMQTVVCDGMASGLDKDYLKPDD (SEQ ID NO: 3518)LSTAADMQTVVTCGMASGLDKDYLKPDD (SEQ ID NO: 3519)LSTAADMQATVTCGMASGLDKDYLKPDD (SEQ ID NO: 3520)LSTAADMQATVTDCMASGLDKDYLKPDD (SEQ ID NO: 3521)LSTAADMQGVTADCMASGLDKDYLKPDD (SEQ ID NO: 3522)LSTAADMQGVTADGCASGLDKDYLKPDD (SEQ ID NO: 3523)LSTAADMQGVVTNGCASGLDKDYLKPDD

A practical approach would be to genetically make a large number of suchsequences and select a group for purification on the basis of extent ofmodification and level of production.

In another embodiment, a thioether bridge is formed between a threonineat position 12 in p28 (SEQ ID NO: 13) and the c-terminus of the peptide.The distance between the Cα of position 13 and the aspartate at position28 might be 17.52 angstroms, larger than 1.5 nanometers, implyingsignificant alteration of the structure of the peptide. (See FIG. 5.)

In another embodiment, the peptide sequence isLSTAADMQGVVTATMGSGLCKDYLKPDD, (SEQ ID NO. 3524) with a thioether bridgefrom position 14 to position 2 at a distance of 4.38 angstroms. Themutation of aspartate at position 13 to alanine favors dehydration ofthreonine at position 14. Mutation of alanine at position 16 to glycinecompletely prevents dehydration of serine at position 17 and enhancescyclization.

In another embodiment, the peptide sequence isLSTAADMQGVVTDLTASGLCKDYLKPDD, (SEQ ID NO. 3525) with the thioetherbridge from position 15 to position 20 at a distance of 5.83 angstroms.In this situation, mutation of glycine at position 14 to leucine favorsdehydration of threonine at position 15.

Tertiary Structure Stabilization

The stability of the tertiary structure of the cupredoxin derivedpeptide will affect most aspects of the pharmacokinetics, including thepharmacologic activity, plasma half-life, and/or immunogenicity amongothers. See Kanovsky et al., Cancer Chemother. Pharmacol. 52:202-208(2003); Kanovsky et al., PNAS 23:12438-12443 (2001). Peptide helicesoften fait apart into random coils, becoming more susceptible toprotease attack and may not penetrate cell membrane well. Schafmeisteret al., J. Am. Chem. Soc. 122:5891-5892(2000). Therefore, one way tostabilize the overall structure of the peptide is to stabilise theα-helix structure of the peptide. The intra-molecular hydrogen bondingassociated with helix formation reduces the exposure of the polar amidebackbone, thereby reducing the barrier to membrane penetration in atransport peptide, and thus increasing related pharmacologic activitiesand increasing the resistance of the peptide to protease cleavage. Id.Pseudomonas aeruginosa azurin (SEQ ID NO: 1) has α-helices at residues53-56, 58-64 and 68-70.

One method to stabilize an α-helix is to replace in the α-helix helixbreaking amino acid residues such as glycine, proline, serine andaspartic acid, or helix neutral amino acid residues such as alanine,threonine, valine, glutamine, asparagine, cysteine, histidine, lysine orarginine, with helix forming residues, such as leucine, isoleucine,phenylalanine, glutamic acid, tyrosine, tryptophan and methionine orhelix favoring amino acid residue substitutions, for exampleα-amino-isobutyric acid (Aib). See Miranda et al., J. Med. Chem., 51,2758-2765 (2008). It is contemplated that the α-helix of cupredoxinderived peptides may be stabilized by replacing one or more glycine,proline, serine and/or aspartic acid residues with other amino acids. Inspecific embodiments, the glycine, proline, serine, aspartic acid,alanine, threonine, valine, glutamine, asparagine, cysteine, histidine,lysine and/or arginine residues are replaced by leucine, isoleucine,phenylalanine, glutamic acid, tyrosine, tryptophan, Aib and/ormethionine residues. See Lee et al., Cancer Cell Intl. 11:21 (2005). Inother specific embodiments, one or more serine or glutamine residues inthe n-helices of a cupredoxin derived peptide may be substituted. Instill more specific embodiments, the serine and/or glutamine residues inresidues 53-56, 58-64 and 68-70 of P. aeruginosa azurin (SEQ ID NO; 1),or equivalent residues of other cupredoxin derived peptides, may bereplaced. In another specific embodiment, the glutamine residue at aminoacid residue 57 of P. aeruginosa azurin (SEQ ID NO: 1), or an equivalentresidue of another cupredoxin derived peptide, may be replaced, morespecifically replaced with tryptophan. In another specific embodiment,the threonine residue at amino acid residue 52 of P. aeruginosa azurin(SEQ ID NO; 1), or an equivalent residue of another cupredoxin derivedpeptide, may be replaced, more specifically replaced with tryptophan. Inanother specific embodiment, the threonine residue at amino acid residue61 of P. aeruginosa azurin (SEQ ID NO; or an equivalent residue ofanother cupredoxin derived peptide, may be replaced, more specificallyreplaced with tryptophan. In another specific embodiment, the glycineresidue al amino acid residue 63 of aeruginosa azurin (SEQ ID NO: 1), oran equivalent residue of another cupredoxin derived peptide, may bereplaced, more specifically replaced with tryptophan. In anotherspecific embodiment, one or more threonine, glutamine or glycineresidues at amino acid residues 52, 57, 61 or 63 of P. aeruginosa azurin(SEQ ID NO; 1), or an equivalent residue of another cupredoxin derivedpeptide, may be replaced, more specifically replaced with tryptophan. Inspecific embodiments, the cupredoxin peptide comprises one of thefollowing sequences wherein the underlined amino acid is substitutedinto the wild type Pseudomonas aeruginosa azurin sequence:

(SEQ ID NO: 34) LSWAADMQGVVTDGMASGLDKDYLKPDD; (SEQ ID NO: 35)LSTAADMWGVVTDGMASGLDKDYLKPDD; (SEQ ID NO: 36)LSTAADMQGVVWDGMASGLDKDYLKPDD; (SEQ ID NO: 37)LSTAADMQGVVTDWMASGLDKDYLKPDD; (SEQ ID NO: 38)LSWAADMWGVVTDGMASGLDKDYLKPDD;In other embodiments, equivalent amino acids in other cupredoxin derivedpeptides are substituted with tryptophan.

Another method to stabilize an α-helix tertiary structure involves usingunnatural amino acid residues capable of π-stacking. For example, inAndrews and Tabor (Tetrahedron 55:11711-11743 (1999)), pairs ofε-(3,5-dinitrobenzoyl)-Lys residues were substituted into the α-helixregion of a peptide at different spacings. The overall results showedthat the i,(i+4) spacing was the most effective stabilizing arrangement.Increasing the percentage of water, up to 90%, increased the helicalcontent of the peptide. Pairs of ε-acyl-Lys residues in the same i,(i+4)spacing had no stabilizing effect, indicating that the majority of thestabilization arises from π-π interactions. In one embodiment, thecupredoxin derived peptide may be modified BO that the lysine residuesare substituted by ε-(3,5-dinitrobenzoyl)-Lys residues. In a specificembodiment, the lysine residues may be substituted byε-(3,5-dinitrobenzoyl)-Lys in a i,(i+4) spacing.

Another method to stabilize an α-helix tertiary structure uses theelectrostatic interactions between side-chains in the α-helix. WhenHis-Cys or His-His residue pairs were substituted in into peptides in ani,(i+4) arrangement, the peptides changed from about 50% helical toabout 90% helical on the addition of Cu, Zn or Cd ions. When ruthenium(Ru) salts were added to the His-His peptides, an exchange-inert complexwas formed, a macrocyclic cis-[Ru—(NH₃)₄L₂]³⁺ complex where L₂ are theside chains of two histidines, which improved the helix stability.Ghadiri and Femholz, J. Am. Chem. Soc. 112, 9633-9635 (1990). In someembodiments, the cupredoxin derived peptides may comprise macrocycliccis-[Ru—(NH₃)₄L₂]³⁺ complexes where L₂ is the side chains of twohistidines. In some embodiments, one or more histidine-cysteine orhistidine-histidine residue pairs may be substituted an i,(i+4)arrangement into the α-helices of the cupredoxin derived peptide. Inother embodiments, one or more histidine-cysteine or histidine-histidineresidue pairs may be substituted an i,(i+4) arrangement in residues53-56, 58-64 and 68-70 of P. aeruginosa azurin (SEQ ID NO: 1), orequivalent residues of other cupredoxin derived peptides. In someembodiments, the cupredoxin derived peptide may further comprise Cu, Zn,Cd and/or Ru ions.

Another method to stabilize an α-helix tertiary structure involvesdisulfide bond formation between side-chains of the α-helix. It is alsopossible to stabilize helical structures by means of formal covalentbonds between residues separated in the peptide sequence. The commonlyemployed natural method is to use disulfide bonds. Pierret et al., Intl.J. Pept. Prot. Res., 46:471-479(1995). In some embodiments, one or morecysteine residue pairs are substituted into the α-helices of thecupredoxin derived peptide. In other embodiments, one or more cysteineresidue pairs are substituted at residues 53-56, 58-64 and 68-70 of P.aeruginosa azurin (SEQ ID NO: 1), or equivalent residues of othercupredoxin derived peptides.

Another method to stabilize an α-helical tertiary structure involves theuse of side chain lactam bridges. A lactam is a cyclic amide which canform from the cyclization of amino acids. Side chain to side chainbridges have been successfully used as constraints in a variety ofpeptides and peptide analogues, such as amphipathic or model α-helicalpeptides, oxytocin antagonists, melanotropin analogues, glucagon, andSDF-1 peptide analogues. For example, the Glucagon-like Peptide-1(GLP-1) gradually assumes a helical conformation under certainhelix-favoring conditions and can be stabilized using lactam bridging.Miranda et al., J. Med. Chem., 51, 2758-2765 (2008). These lactambridges may be varied in size, effecting stability and binding affinity.Id. Such modifications improved the stability of the compounds inplasma, id. Depending on the space between the cyclization sites andchoice of residues, lactam bridges can be used to induce and stabilizeturn or helical conformations. In some embodiments, one or morecupredoxin or variant analogues are prepared with lactam bridgingbetween nearby amino acids (such as i to i+4 glutamic acid-lysineconstraints). In some embodiments, the cupredoxin derived peptide maycomprise such modifications to enhance α-helix content.

Another method to stabilize an α-helix tertiary structure is theail-carbon cross-link method. The all-hydrocarbon cross-link method isproven to increase the stabilization of helical structure, proteaseresistant and cell-permeability. Walensky et al., Science, 305,1466-1470 (2004). α,α-disubstituted non-natural amino acids containingolefin-bearing tethers are incorporated into peptides. Rutheniumcatalyzed olefin metathesis generates an all-hydrocarbon “staple” tocross-link the helix. Schafmeister et al., J. Am. Chem. Soc., 122,5891-5892 (2000); Walensky et al., id. Non-natural amino acidscontaining olefin-bearing tethers may be synthesized according tomethodology provided in Schafmeister et at (id.) and Williams and Im (J.Am Chem. Soc., 113:9276-9286(1991)). In some embodiments, me cupredoxinderived peptides are stabilized by all-hydrocarbon staples. In specificembodiments, one or more pairs of α,α-disubstituted non-natural aminoacids containing olefin-bearing tethers corresponding to the nativeamino acids are substituted into the α-helices of the cupredoxin derivedpeptide. In other embodiments, one or more pairs of α,α-disubstitutednon-natural amino acids containing olefin-bearing tethers correspondedto the native amino acids are substituted into residues 53-56, 58-64 and68-70 of P. aeruginosa azurin (SEQ ID NO; 1), or equivalent residues ofother cupredoxin derived peptides.

In some embodiments, the modified cupredoxin derived peptide maycomprise X₁SX₂AADX₃X₄X₅VVX₆DX₇X₈ASGLDKDYLKPDX₉ (SEQ ID NO:48), where X₁is L or acetylated-L, X₂ is T or W, X₃ is M, t or V, X₄ is Q or W, X₅ isG or A, X₆ is T or W, X₇ is G; T or W, X₈ is M, L or V, and X₉ is D oramidated-D. In other embodiments, the modified cupredoxin derivedpeptide may consist of X₁SX₂AADX₃X₄X₅VVX₆DX₇X₈ASGLDKDYLKPDX₉ (SEQ IDNO:48), where X₁ is L or acetylated-L, X₂ is T or W, X₃ is M, L or V, X₄is Q or W, X₅ is G or A, X₆ is T or W, X₇ is G, T or W, X₈ is M, L or V,and X₉ is D or amidated-D. In other embodiments, the modified cupredoxinderived peptide may comprise X₁DPKLYDKDLGSAX₂X₃DX₄VVX₅X₆X₇DAAX₈SX₉ (SEQID NO:49), where X₁ is D or acetylated-D, X₂ is M, L or V, X₃ is G, T orW, X₄ is T or W, X₅ is G or A, X₆ is Q or W, X₇ is M, L or V, X₈ is T orW, and X₉ is L or amidated-L. In other embodiments, the modifiedcupredoxin derived peptide may consist ofX₁DPKLYDKDLGSAX₂X₃DX₄VVX₅X₆X₇DAAX₈SX₉(SEQ ID NO:49), where X₁ is D oracetylated-D, X₂ is M, L or V, X₃ is G, T or W, X₄ is T or W, X₅ is G orA, X₆ is Q or W, X₇ is M, L or V, X₈ is T or W, and X₉ is L oramidated-L. Specific peptides of interest are listed in Table 3.

TABLE 3  Modified Curedoxin-Derived Peptides*LSTAADMQGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 50)LSWAADMQGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 51)*LSWAADMQGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 52)LSTAADLQGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 53)*LSTAADLQGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 54)LSWAADLQGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 55)*LSWAADLQGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 56)LSTAADVQGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 57)*LSTAADVQGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 58)LSWAADVQGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 59)*LSWAADVQGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 60)LSTAADMWGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 61)*LSTAADMWGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 62)LSWAADMWGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 63)*LSWAADMWGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 64)LSTAADLWGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 65)*LSTAADLWGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 66)LSWAADLWGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 67)*LSWAADLWGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 68)LSTAADVWGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 69)*LSTAADVWGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 70)LSWAADVWGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 71)*LSWAADVWGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 72)LSTAADMQAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 73)*LSTAADMQAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 74)LSWAADMQAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 75)*LSWAADMQAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 76)LSTAADLQAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 77)*LSTAADLQAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 78)LSWAADLQAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 79)*LSWAADLQAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 80)LSTAADVQAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 81)*LSTAADVQAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 82)LSWAADVQAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 83)*LSWAADVQAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 84)LSTAADMWAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 85)*LSTAADMWAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 86)LSWAADMWAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 87)*LSWAADMWAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 88)LSTAADLWAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 89)*LSTAADLWAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 90)LSWAADLWAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 91)*LSWAADLWAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 92)LSTAADVWAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 93)*LSTAADVWAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 94)LSWAADVWAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 95)*LSWAADVWAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 96)LSTAADMQGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 97)*LSTAADMQGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 98)LSWAADMQGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 99)*LSWAADMQGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 100)LSTAADLQGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 101)*LSTAADLQGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 102)LSWAADLQGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 103)*LSWAADLQGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 104)LSTAADVQGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 105)*LSTAADVQGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 106)LSWAADVQGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 107)*LSWAADVQGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 108)LSTAADMWGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 109)*LSTAADMWGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 110)LSWAADMWGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 111)*LSWAADMWGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 112)LSTAADLWGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 113)*LSTAADLWGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 114)LSWAADLWGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 115)*LSWAADLWGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 116)LSTAADVWGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 117)*LSTAADVWGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 118)LSWAADVWGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 119)*LSWAADVWGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 120)LSTAADMQAVVWDGMASGLDKDYLKPDD (SEQ ID NO: 121)*LSTAADMQAVVWDGMASGLDKDYLKPDD (SEQ ID NO: 122)LSWAADMQAVVWDGMASGLDKDYLKPDD (SEQ ID NO: 123)*LSWAADMQAVVWDGMASGLDKDYLKPDD (SEQ ID NO: 124)LSTAADLQAVVWDGMASGLDKDYLKPDD (SEQ ID NO: 125)*LSTAADLQAVVWDGMASGLDKDYLKPDD (SEQ ID NO: 126)LSWAADLQAVVWDGMASGLDKDYLKPDD (SEQ ID NO: 127)*LSWAADLQAVVWDGMASGLDKDYLKPDD (SEQ ID NO: 128)LSTAADVQAVVWDGMASGLDKDYLKPDD (SEQ ID NO: 129)*LSTAADVQAVVWDGMASGLDKDYLKPDD (SEQ ID NO: 130)LSWAADVQAVVWDGMASGLDKDYLKPDD (SEQ ID NO: 131)*LSWAADVQAVVWDGMASGLDKDYLKPDD (SEQ ID NO: 132)LSTAADMWAVVWDGMASGLDKDYLKPDD (SEQ ID NO: 133)*LSTAADMWAVVWDGMASGLDKDYLKPDD (SEQ ID NO: 134)LSWAADMWAVVWDGMASGLDKDYLKPDD (SEQ ID NO: 135)*LSWAADMWAVVWDGMASGLDKDYLKPDD (SEQ ID NO: 136)LSTAADLWAVVWDGMASGLDKDYLKPDD (SEQ ID NO: 137)*LSTAADLWAVVWDGMASGLDKDYLKPDD (SEQ ID NO: 138)LSWAADLWAVVWDGMASGLDKDYLKPDD (SEQ ID NO: 139)*LSWAADLWAVVWDGMASGLDKDYLKPDD (SEQ ID NO: 140)LSTAADVWAVVWDGMASGLDKDYLKPDD (SEQ ID NO: 141)*LSTAADVWAVVWDGMASGLDKDYLKPDD (SEQ ID NO: 142)LSWAADVWAVVWDGMASGLDKDYLKPDD (SEQ ID NO: 143)*LSWAADVWAVVWDGMASGLDKDYLKPDD (SEQ ID NO: 144)LSTAADMQGVVTDTMASGLDKDYLKPDD (SEQ ID NO: 145)*LSTAADMQGVVTDTMASGLDKDYLKPDD (SEQ ID NO: 146)LSWAADMQGVVTDTMASGLDKDYLKPDD (SEQ ID NO: 147)*LSWAADMQGVVTDTMASGLDKDYLKPDD (SEQ ID NO: 148)LSTAADLQGVVTDTMASGLDKDYLKPDD (SEQ ID NO: 149)*LSTAADLQGVVTDTMASGLDKDYLKPDD (SEQ ID NO: 150)LSWAADLQGVVTDTMASGLDKDYLKPDD (SEQ ID NO: 151)*LSWAADLQGVVTDTMASGLDKDYLKPDD (SEQ ID NO: 152)LSTAADVQGVVTDTMASGLDKDYLKPDD (SEQ ID NO: 153)*LSTAADVQGVVTDTMASGLDKDYLKPDD (SEQ ID NO: 154)LSWAADVQGVVTDTMASGLDKDYLKPDD (SEQ ID NO: 155)*LSWAADVQGVVTDTMASGLDKDYLKPDD (SEQ ID NO: 156)LSTAADMWGVVTDTMASGLDKDYLKPDD (SEQ ID NO: 157)*LSTAADMWGVVTDTMASGLDKDYLKPDD (SEQ ID NO: 158)LSWAADMWGVVTDTMASGLDKDYLKPDD (SEQ ID NO: 159)*LSWAADMWGVVTDTMASGLDKDYLKPDD (SEQ ID NO: 160)LSTAADLQGVVTDTMASGLDKDYLKPDD (SEQ ID NO: 161)*LSTAADLQGVVTDTMASGLDKDYLKPDD (SEQ ID NO: 162)LSWAADLQGVVTDTMASGLDKDYLKPDD (SEQ ID NO: 163)*LSWAADLQGVVTDTMASGLDKDYLKPDD (SEQ ID NO: 164)LSTAADVWGVVTDTMASGLDKDYLKPDD (SEQ ID NO: 165)*LSTAADVWGVVTDTMASGLDKDYLKPDD (SEQ ID NO: 166)LSWAADVWGVVTDTMASGLDKDYLKPDD (SEQ ID NO: 167)*LSWAADVWGVVTDTMASGLDKDYLKPDD (SEQ ID NO: 168)LSTAADMQAVVTDTMASGLDKDYLKPDD (SEQ ID NO: 169)*LSTAADMQAVVTDTMASGLDKDYLKPDD (SEQ ID NO: 170)LSWAADMQAVVTDTMASGLDKDYLKPDD (SEQ ID NO: 171)*LSWAADMQAVVTDTMASGLDKDYLKPDD (SEQ ID NO: 172)LSTAADLQAVVTDTMASGLDKDYLKPDD (SEQ ID NO: 173)*LSTAADLQAVVTDTMASGLDKDYLKPDD (SEQ ID NO: 174)LSWAADLQAVVTDTMASGLDKDYLKPDD (SEQ ID NO: 175)*LSWAADLQAVVTDTMASGLDKDYLKPDD (SEQ ID NO: 176)LSTAADVQAVVTDTMASGLDKDYLKPDD (SEQ ID NO: 177)*LSTAADVQAVVTDTMASGLDKDYLKPDD (SEQ ID NO: 178)LSWAADVQAVVTDTMASGLDKDYLKPDD (SEQ ID NO: 179)*LSWAADVQAVVTDTMASGLDKDYLKPDD (SEQ ID NO: 180)LSTAADMWAVVTDTMASGLDKDYLKPDD (SEQ ID NO: 181)*LSTAADMWAVVTDTMASGLDKDYLKPDD (SEQ ID NO: 182)LSWAADMWAVVTDTMASGLDKDYLKPDD (SEQ ID NO: 183)*LSWAADMWAVVTDTMASGLDKDYLKPDD (SEQ ID NO: 184)LSTAADLWAVVTDTMASGLDKDYLKPDD (SEQ ID NO: 185)*LSTAADLWAVVTDTMASGLDKDYLKPDD (SEQ ID NO: 186)LSWAADLWAVVTDTMASGLDKDYLKPDD (SEQ ID NO: 187)*LSWAADLWAVVTDTMASGLDKDYLKPDD (SEQ ID NO: 188)LSTAADVWAVVTDTMASGLDKDYLKPDD (SEQ ID NO: 189)*LSTAADVWAVVTDTMASGLDKDYLKPDD (SEQ ID NO: 190)LSWAADVWAVVTDTMASGLDKDYLKPDD (SEQ ID NO: 191)*LSWAADVWAVVTDTMASGLDKDYLKPDD (SEQ ID NO: 192)LSTAADMQGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 193)*LSTAADMQGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 194)LSWAADMQGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 195)*LSWAADMQGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 196)LSTAADMQGVVWDTASGLDKDYLKPDD (SEQ ID NO: 197)*LSTAADMQGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 198)LSWAADMQGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 199)*LSWAADMQGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 200)LSTAADVQGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 201)*LSTAADVQGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 202)LSWAADVQGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 203)*LSWAADVQGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 204)LSTAADMWGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 205)*LSTAADMWGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 206)LSWAADMWGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 207)*LSWAADMWGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 208)LSTAADLWGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 209)*LSTAADLWGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 210)LSWAADLWGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 211)*LSWAADLWGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 212)LSTAADVWGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 213)*LSTAADVWGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 214)LSWAADVWGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 215)*LSWAADVWGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 216)LSTAADMQAVVWDTMASGLDKDYLKPDD (SEQ ID NO: 217)*LSTAADMAGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 218)LSWAADMAGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 219)*LSWAADMAGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 220)LSTAADLQAVVWDTMASGLDKDYLKPDD (SEQ ID NO: 221)*LSTAADLQAVVWDTMASGLDKDYLKPDD (SEQ ID NO: 222)LSWAADLQGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 223)*LSWAADLQGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 224)LSTAADVQGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 225)*LSTAADVQGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 226)LSWAADVQGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 227)*LSWAADVQGVVWDTMASGLDKDYLKPDD (SEQ ID NO: 228)LSTAADMWAVVWDTMASGLDKDYLKPDD (SEQ ID NO: 229)*LSTAADMWAVVWDTMASGLDKDYLKPDD (SEQ ID NO: 230)LSWAADMWAVVWDTMASGLDKDYLKPDD (SEQ ID NO: 231)*LSWAADMWAVVWDTMASGLDKDYLKPDD (SEQ ID NO: 232)LSTAADMWAVVWDTMASGLDKDYLKPDD (SEQ ID NO: 233)*LSTAADMWAVVWDTMASGLDKDYLKPDD (SEQ ID NO: 234)LSWAADMWAVVWDTMASGLDKDYLKPDD (SEQ ID NO: 235)*LSWAADMWAVVWDTMASGLDKDYLKPDD (SEQ ID NO: 236)LSTAADVWAVVWDTMASGLDKDYLKPDD (SEQ ID NO: 237)*LSTAADVWAVVWDTMASGLDKDYLKPDD (SEQ ID NO: 238)LSWAADVWAVVWDTMASGLDKDYLKPDD (SEQ ID NO: 239)*LSWAADVWAVVWDTMASGLDKDYLKPDD (SEQ ID NO: 240)LSTAADMQGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 241)*LSTAADMQGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 242)LSWAADMQGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 243)*LSWAADMQGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 244)LSTAADLQGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 245)*LSTAADLQGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 246)LSWAADLQGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 247)*LSWAADLQGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 248)LSTAADVQGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 249)*LSTAADVQGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 250)LSWAADVQGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 251)*LSWAADVQGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 252)LSTAADMWGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 253)*LSTAADMWGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 254)LSWAADMWGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 255)*LSWAADMWGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 256)LSTAADLWGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 257)*LSTAADLWGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 258)LSWAADLWGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 259)*LSWAADLWGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 260)LSTAADVWGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 261)*LSTAADVWGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 262)LSWAADVWGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 263)*LSWAADVWGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 264)LSTAADMQGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 265)*LSTAADMQGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 266)LSWAADMQGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 267)*LSWAADMQGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 268)LSTAADLQGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 269)*LSTAADLQGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 270)LSWAADLQGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 271)*LSWAADLQGVVTDWMASGLDKDYLKPDD (SEQ ID NO: 272)LSTAADVQAVVTDWMASGLDKDYLKPDD (SEQ ID NO: 273)*LSTAADVQAVVTDWMASGLDKDYLKPDD (SEQ ID NO: 274)LSWAADVQAVVTDWMASGLDKDYLKPDD (SEQ ID NO: 275)*LSWAADVQAVVTDWMASGLDKDYLKPDD (SEQ ID NO: 276)LSTAADMWAVVTDWMASGLDKDYLKPDD (SEQ ID NO: 277)*LSTAADMWAVVTDWMASGLDKDYLKPDD (SEQ ID NO: 278)LSWAADMWAVVTDWMASGLDKDYLKPDD (SEQ ID NO: 279)*LSWAADMWAVVTDWMASGLDKDYLKPDD (SEQ ID NO: 280)LSTAADLWAVVTDWMASGLDKDYLKPDD (SEQ ID NO: 281)*LSTAADLWAVVTDWMASGLDKDYLKPDD (SEQ ID NO: 282)LSWAADLWAVVTDWMASGLDKDYLKPDD (SEQ ID NO: 283)*LSWAADLWAVVTDWMASGLDKDYLKPDD (SEQ ID NO: 284)LSTAADVWAVVTDWMASGLDKDYLKPDD (SEQ ID NO: 285)*LSTAADVWAVVTDWMASGLDKDYLKPDD (SEQ ID NO: 286)LSWAADVWAVVTDWMASGLDKDYLKPDD (SEQ ID NO: 287)*LSWAADVWAVVTDWMASGLDKDYLKPDD (SEQ ID NO: 288)LSTAADMQGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 289)*LSTAADMQGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 290)LSWAADMQGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 291)*LSWAADMQGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 292)LSTAADLQGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 293)*LSTAADLQGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 294)LSWAADLQGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 295)*LSWAADLQGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 296)LSTAADVQGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 297)*LSTAADVQGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 298)LSWAADVQGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 299)*LSWAADVQGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 300)LSTAADMWGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 301)*LSTAADMWGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 302)LSWAADMWGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 303)*LSWAADMQGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 304)LSTAADLWGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 305)*LSTAADLWGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 306)LSWAADLWGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 307)*LSWAADLWGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 308)LSTAADVWGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 309)*LSTAADVWGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 310)LSWAADVWGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 311)*LSWAADVWGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 312)LSTAADMQAVVWDWMASGLDKDYLKPDD (SEQ ID NO: 313)*LSTAADMQAVVWDWMASGLDKDYLKPDD (SEQ ID NO: 314)LSWAADMQAVVWDWMASGLDKDYLKPDD (SEQ ID NO: 315)*LSWAADMQAVVWDWMASGLDKDYLKPDD (SEQ ID NO: 316)LSTAADLQAVVWDWMASGLDKDYLKPDD (SEQ ID NO: 317)*LSTAADLQAVVWDWMASGLDKDYLKPDD (SEQ ID NO: 318)LSWAADLQAVVWDWMASGLDKDYLKPDD (SEQ ID NO: 319)*LSWAADLQAVVWDWMASGLDKDYLKPDD (SEQ ID NO: 320)LSTAADVQAVVWDWMASGLDKDYLKPDD (SEQ ID NO: 321)*LSTAADVQAVVWDWMASGLDKDYLKPDD (SEQ ID NO: 322)LSWAADVQGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 323)*LSWAADVQGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 324)LSTAADMQGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 325)*LSTAADMQGVVWDWMASGLDKDYLKPDD (SEQ ID NO: 326)LSWAADMWAVVWEDWMASGLDKDYLKPDD (SEQ ID NO: 327)*LSWAADMWAVVWDWMASGLDKDYLKPDD (SEQ ID NO: 328)LSTAADLwAVVWDWMASGLDKDYLKPDD (SEQ ID NO: 329)*LSTAADLWAVVWDWMASGLDKDYLKPDD (SEQ ID NO: 330)LSWAADLWAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 331)*LSWAADLWAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 332)LSTAADVWAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 333)*LSTAADVWAVVTDGMASGLDKDYLKPDD (SEQ ID NO: 334)LSWAADVWAVVWDWMASGLDKDYLKPDD (SEQ ID NO: 335)*LSWAADVWAVVWDWMASGLDKDYLKPDD (SEQ ID NO: 336)LSTAADMQGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 337)*LSTAADMQGVVTDGMASGLDKDYLKPDD (SEQ ID NO: 338)LSWAADMQGVVTDGLASGLDKDYLKPDD (SEQ ID NO: 339)*LSWAADMQGVVTDGLASGLDKDYLKPDD (SEQ ID NO: 340)LSTAADLQGVVTDGLASGLDKDYLKPDD (SEQ ID NO: 341)*LSTAADLQGVVTDGLASGLDKDYLKPDD (SEQ ID NO: 342)LSWAADLQGVVTDGLASGLDKDYLKPDD (SEQ ID NO: 343)*LSWAADLQGVVTDGLASGLDKDYLKPDD (SEQ ID NO: 344)LSTAADVQGVVTDGLASGLDKDYLKPDD (SEQ ID NO: 345)*LSTAADVQGVVTDGLASGLDKDYLKPDD (SEQ ID NO: 346)LSWAADVQGVVTDGLASGLDKDYLKPDD (SEQ ID NO: 347)*LSWAADVQGVVTDGLASGLDKDYLKPDD (SEQ ID NO: 348)LSTAADWQGVVTDGLASGLDKDYLKPDD (SEQ ID NO: 349)*LSTAADWQGVVTDGLASGLDKDYLKPDD (SEQ ID NO: 350)LSWAADMWGVVTDGLASGLDKDYLKPDD (SEQ ID NO: 351)*LSWAADMWGVVTDGLASGLDKDYLKPDD (SEQ ID NO: 352)LSTAADLWGVVTDGLASGLDKDYLKPDD (SEQ ID NO: 353)*LSTAADLWGVVTDGLASGLDKDYLKPDD (SEQ ID NO: 354)LSWAADLWGVVTDGLASGLDKDYLKPDD (SEQ ID NO: 355)*LSWAADLWGVVTDGLASGLDKDYLKPDD (SEQ ID NO: 356)LSTAADVWGVVTDGLASGLDKDYLKPDD (SEQ ID NO: 357)*LSTAADVWGVVTDGLASGLDKDYLKPDD (SEQ ID NO: 358)LSWAADVWGVVTDGLASGLDKDYLKPDD (SEQ ID NO: 359)*LSWAADVWGVVTDGLASGLDKDYLKPDD (SEQ ID NO: 360)LSTAADMQAVVTDGLASGLDKDYLKPDD (SEQ ID NO: 361)*LSTAADMQAVVTDGLASGLDKDYLKPDD (SEQ ID NO: 362)LSWAADMQAVVTDGLASGLDKDYLKPDD (SEQ ID NO: 363)*LSWAADMQAVVTDGLASGLDKDYLKPDD (SEQ ID NO: 364)LSTAADMQAVVTDGLASGLDKDYLKPDD (SEQ ID NO: 365)*LSTAADMQAVVTDGLASGLDKDYLKPDD (SEQ ID NO: 366)LSWAADMQAVVTDGLASGLDKDYLKPDD (SEQ ID NO: 367)*LSWAADMQAVVTDGLASGLDKDYLKPDD (SEQ ID NO: 368)LSTAADVQAVVTDGLASGLDKDYLKPDD (SEQ ID NO: 369)*LSTAADVQAVVTDGLASGLDKDYLKPDD (SEQ ID NO: 370)LSWAADVQAVVTDGLASGLDKDYLKPDD (SEQ ID NO: 371)*LSWAADVQAVVTDGLASGLDKDYLKPDD (SEQ ID NO: 372)LSTAADMWAVVTDGLASGLDKDYLKPDD (SEQ ID NO: 373)*LSTAADMWAVVTDGLASGLDKDYLKPDD (SEQ ID NO: 374)LSWAADMWAVVTDGLASGLDKDYLKPDD (SEQ ID NO: 375)*LSWAADMWAVVTDGLASGLDKDYLKPDD (SEQ ID NO: 376)LSTAADLWAVVTDGLASGLDKDYLKPDD (SEQ ID NO: 377)*LSTAADLWAVVTDGLASGLDKDYLKPDD (SEQ ID NO: 378)LSWAADLWAVVTDGLASGLDKDYLKPDD (SEQ ID NO: 379)*LSWAADLWAVVTDGLASGLDKDYLKPDD (SEQ ID NO: 380)LSTAADVWAVVTDGLASGLDKDYLKPDD (SEQ ID NO: 381)*LSTAADVWAVVTDGLASGLDKDYLKPDD (SEQ ID NO: 382)LSWAADVWAVVTDGLASGLDKDYLKPDD (SEQ ID NO: 383)*LSWAADVWAVVTDGLASGLDKDYLKPDD (SEQ ID NO: 384)LSTAADMQGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 385)*LSTAADMQGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 386)LSWAADMQGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 387)*LSWAADMQGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 388)LSTAADLQGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 389)*LSTAADLQGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 390)LSWAADLQGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 391)*LSWAADLQGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 392)LSTAADVQGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 393)*LSTAADVQGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 394)LSWAADVQGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 395)*LSWAADVQGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 396)LSTAADMWGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 397)*LSTAADMWGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 398)LSWAADMWGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 399)*LSWAADMWGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 400)LSTAADLWGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 401)*LSTAADLWGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 402)LSWAADLWGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 403)*LSWAADLWGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 404)LSTAADVWGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 405)*LSTAADVWGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 406)LSWAADVWGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 407)*LSWAADVWGVVWDGMASGLDKDYLKPDD (SEQ ID NO: 408)LSTAADMQAVVWDGLASGLDKDYLKPDD (SEQ ID NO: 409)*LSTAADMQAVVWDGLASGLDKDYLKPDD (SEQ ID NO: 410)LSWAADMQAVVWDGLASGLDKDYLKPDD (SEQ ID NO: 411)*LSWAADMQAVVWDGLASGLDKDYLKPDD (SEQ ID NO: 412)LSTAADLQGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 413)*LSTAADLQGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 414)LSWAADLQGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 415)*LSWAADLQGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 416)LSTAADVQGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 417)*LSTAADVQGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 418)LSWAADVQGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 419)*LSWAADVQGVVWDGLASGLDKDYLKPDD (SEQ ID NO: 420)LSTAADMWAVVWDGLASGLDKDYLKPDD (SEQ ID NO: 421)*LSTAADMWAVVWDGLASGLDKDYLKPDD (SEQ ID NO: 422)LSWAADMWAVVWDGLASGLDKDYLKPDD (SEQ ID NO: 423)*LSWAADMWAVVWDGLASGLDKDYLKPDD (SEQ ID NO: 424)LSTAADLWAVVWDGLASGLDKDYLKPDD (SEQ ID NO: 425)*LSTAADLWAVVWDGLASGLDKDYLKPDD (SEQ ID NO: 426)LSWAADLWAVVWDGLASGLDKDYLKPDD (SEQ ID NO: 427)*LSWAADLWAVVWDGLASGLDKDYLKPDD (SEQ ID NO: 428)LSTAADVWAVVWDGLASGLDKDYLKPDD (SEQ ID NO: 429)*LSTAADVWAVVWDGLASGLDKDYLKPDD (SEQ ID NO: 430)LSWAADVWAVVWDGLASGLDKDYLKPDD (SEQ ID NO: 431)*LSWAADVWAVVWDGLASGLDKDYLKPDD (SEQ ID NO: 432)LSTAADMQGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 433)*LSTAADMQGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 434)LSWAADMQGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 435)*LSWAADMQGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 436)LSTAADLQGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 437)*LSTAADLQGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 438)LSWAADLQGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 439)*LSWAADLQGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 440)LSTAADVQGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 441)*LSTAADVQGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 442)LSWAADVQGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 443)*LSWAADVQGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 444)LSTAADMWGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 445)*LSTAADMWGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 446)LSWAADMWGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 447)*LSWAADMWGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 448)LSTAADLWGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 449)*LSTAADLWGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 450)LSWAADLWGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 451)*LSWAADLWGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 452)LSTAADVWGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 453)*LSTAADVWGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 454)LSWAADVWGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 455)*LSWAADVWGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 456)LSTAADMQGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 457)*LSTAADMQGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 458)LSWAADMQGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 459)*LSWAADMQGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 460)LSTAADLQGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 461)*LSTAADLQGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 462)LSWAADLQGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 463)*LSWAADLQGVVTDTLASGLDKDYLKPDD (SEQ ID NO: 464)LSTAADVQAVVTDTLASGLDKDYLKPDD (SEQ ID NO: 465)*LSTAADVQAVVTDTLASGLDKDYLKPDD (SEQ ID NO: 466)LSWAADVQAVVTDTLASGLDKDYLKPDD (SEQ ID NO: 467)*LSWAADVQAVVTDTLASGLDKDYLKPDD (SEQ ID NO: 468)LSTAADMWAVVTDTLASGLDKDYLKPDD (SEQ ID NO: 469)*LSTAADMWAVVTDTLASGLDKDYLKPDD (SEQ ID NO: 470)LSWAADMWAVVTDTLASGLDKDYLKPDD (SEQ ID NO: 471)*LSWAADMWAVVTDTLASGLDKDYLKPDD (SEQ ID NO: 472)LSTAADLWAVVTDTLASGLDKDYLKPDD (SEQ ID NO: 473)*LSTAADLWAVVTDTLASGLDKDYLKPDD (SEQ ID NO: 474)LSWAADLWAVVTDTLASGLDKDYLKPDD (SEQ ID NO: 475)*LSWAADLWAVVTDTLASGLDKDYLKPDD (SEQ ID NO: 476)LSTAADVWAVVTDTLASGLDKDYLKPDD (SEQ ID NO: 477)*LSTAADVWAVVTDTLASGLDKDYLKPDD (SEQ ID NO: 478)LSWAADVWAVVTDTLASGLDKDYLKPDD (SEQ ID NO: 479)*LSWAADVWAVVTDTLASGLDKDYLKPDD (SEQ ID NO: 480)LSTAADMQGVVWDTLASGLDKDYLKPDD (SEQ ID NO: 481)*LSTAADMQGVVWDTLASGLDKDYLKPDD (SEQ ID NO: 482)LSWAADMQGVVWDTLASGLDKDYLKPDD (SEQ ID NO: 483)*LSWAADMQGVVWDTLASGLDKDYLKPDD (SEQ ID NO: 484)LSTAADLQGVVWDTLASGLDKDYLKPDD (SEQ ID NO: 485)*LSTAADLQGVVWDTLASGLDKDYLKPDD (SEQ ID NO: 486)LSWAADLQGVVWDTLASGLDKDYLKPDD (SEQ ID NO: 487)*LSWAADLQGVVWDTLASGLDKDYLKPDD (SEQ ID NO: 488)LSTAADVQGVVWDTLASGLDKDYLKPDD (SEQ ID NO: 489)*LSTAADVQGVVWDTLASGLDKDYLKPDD (SEQ ID NO: 490)LSWAADVQGVVWDTLASGLDKDYLKPDD (SEQ ID NO: 491)*LSWAADVQGVVWDTLASGLDKDYLKPDD (SEQ ID NO: 492)LSTAADMWGVVWDTLASGLDKDYLKPDD (SEQ ID NO: 493)*LSTAADMWGVVWDTLASGLDKDYLKPDD (SEQ ID NO: 494)LSWAADMWGVVWDTLASGLDKDYLKPDD (SEQ ID NO: 495)*LSWAADMWGVVWDTLASGLDKDYLKPDD (SEQ ID NO: 496)LSTAADLWGVVWDTLASGLDKDYLKPDD (SEQ ID NO: 497)*LSTAADLWGVVWDTLASGLDKDYLKPDD (SEQ ID NO: 498)LSWAADLWGVVWDTLASGLDKDYLKPDD (SEQ ID NO: 499)*LSWAADLWGVVWDTLASGLDKDYLKPDD (SEQ ID NO: 500)LSTAADVWGVVWDTLASGLDKDYLKPDD (SEQ ID NO: 501)*LSTAADVWGVVWDTLASGLDKDYLKPDD (SEQ ID NO: 502)LSWAADVWGVVWDTLASGLDKDYLKPDD (SEQ ID NO: 503)*LSWAADVWGVVWDTLASGLDKDYLKPDD (SEQ ID NO: 504)LSTAADMQAVVWDTLASGLDKDYLKPDD (SEQ ID NO: 505)*LSTAADMQAVVWDTLASGLDKDYLKPDD (SEQ ID NO: 506)LSWAADMQAVVWDTLASGLDKDYLKPDD (SEQ ID NO: 507)*LSWAADMQAVVWDTLASGLDKDYLKPDD (SEQ ID NO: 508)LSTAADLQAVVWDTLASGLDKDYLKPDD (SEQ ID NO: 509)*LSTAADLQAVVWDTLASGLDKDYLKPDD (SEQ ID NO: 510)LSWAADLQAVVWDTLASGLDKDYLKPDD (SEQ ID NO: 511)*LSWAADLQAVVWDTLASGLDKDYLKPDD (SEQ ID NO: 512)LSTAADVQAVVWDTLASGLDKDYLKPDD (SEQ ID NO: 513)*LSTAADVQAVVWDTLASGLDKDYLKPDD (SEQ ID NO: 514)LSWAADVQAVVWDTLASGLDKDYLKPDD (SEQ ID NO: 515)*LSWAADVQAVVWDTLASGLDKDYLKPDD (SEQ ID NO: 516)LSTAADMWAVVWDTLASGLDKDYLKPDD (SEQ ID NO: 517)*LSTAADMWAVVWDTLASGLDKDYLKPDD (SEQ ID NO: 518)LSWAADMWAVVWDTLASGLDKDYLKPDD (SEQ ID NO: 519)*LSWAADMWAVVWDTLASGLDKDYLKPDD (SEQ ID NO: 520)LSTAADLWAVVWDTLASGLDKDYLKPDD (SEQ ID NO: 521)*LSTAADLWAVVWDTLASGLDKDYLKPDD (SEQ ID NO: 522)LSWAADLWAVVWDTLASGLDKDYLKPDD (SEQ ID NO: 523)*LSWAADLWAVVWDTLASGLDKDYLKPDD (SEQ ID NO: 524)LSTAADVWAVVWDTLASGLDKDYLKPDD (SEQ ID NO: 525)*LSTAADVWAVVWDTLASGLDKDYLKPDD (SEQ ID NO: 526)LSWAADVWAVVWDTLASGLDKDYLKPDD (SEQ ID NO: 527)*LSWAADVWAVVWDTLASGLDKDYLKPDD (SEQ ID NO: 528)LSTAADMQGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 529)*LSTAADMQGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 530)LSWAADMQGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 531)*LSWAADMQGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 532)LSTAADLQGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 533)*LSTAADLQGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 534)LSWAADLQGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 535)*LSWAADLQGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 536)LSTAADVQGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 537)*LSTAADVQGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 538)LSWAADVQGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 539)*LSWAADVQGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 540)LSTAADMWGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 541)*LSTAADMWGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 542)LSWAADMWGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 543)*LSWAADMWGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 544)LSTAADLWGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 545)*LSTAADLWGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 546)LSWAADLWGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 547)*LSWAADLWGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 548)LSTAADVWGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 549)*LSTAADVWGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 550)LSWAADVWGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 551)*LSWAADVWGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 552)LSTAADMQGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 553)*LSTAADMQGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 554)LSWAADMQGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 555)*LSWAADMQGVVTDWLASGLDKDYLKPDD (SEQ ID NO: 556)LSTAADLQAVVTDWLASGLDKDYLKPDD (SEQ ID NO: 557)*LSTAADLQAVVTDWLASGLDKDYLKPDD (SEQ ID NO: 558)LSWAADLQAVVTDWLASGLDKDYLKPDD (SEQ ID NO: 559)*LSWAADLQAVVTDWLASGLDKDYLKPDD (SEQ ID NO: 560)LSTAADVQAVVTDWLASGLDKDYLKPDD (SEQ ID NO: 561)*LSTAADVQAVVTDWLASGLDKDYLKPDD (SEQ ID NO: 562)LSWAADVQAVVTDWLASGLDKDYLKPDD (SEQ ID NO: 563)*LSWAADVQAVVTDWLASGLDKDYLKPDD (SEQ ID NO: 564)LSTAADMWAVVTDWLASGLDKDYLKPDD (SEQ ID NO: 565)*LSTAADMWAVVTDWLASGLDKDYLKPDD (SEQ ID NO: 566)LSWAADMWAVVTDWLASGLDKDYLKPDD (SEQ ID NO: 567)*LSWAADMWAVVTDWLASGLDKDYLKPDD (SEQ ID NO: 568)LSTAADLWAVVTDWLASGLDKDYLKPDD (SEQ ID NO: 569)*LSTAADLWAVVTDWLASGLDKDYLKPDD (SEQ ID NO: 570)LSWAADLWAVVTDWLASGLDKDYLKPDD (SEQ ID NO: 571)*LSWAADLWAVVTDWLASGLDKDYLKPDD (SEQ ID NO: 572)LSTAADVWAVVTDWLASGLDKDYLKPDD (SEQ ID NO: 573)*LSTAADVWAVVTDWLASGLDKDYLKPDD (SEQ ID NO: 574)LSWAADVWAVVTDWLASGLDKDYLKPDD (SEQ ID NO: 575)*LSWAADVWAVVTDWLASGLDKDYLKPDD (SEQ ID NO: 576)LSTAADMQGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 577)*LSTAADMQGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 578)LSWAADMQGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 579)*LSWAADMQGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 580)LSTAADLQGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 581)*LSTAADLQGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 582)LSWAADLQGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 583)*LSWAADLQGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 584)LSTAADVQGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 585)*LSTAADVQGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 586)LSWAADVQGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 587)*LSWAADVQGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 588)LSTAADMWGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 589)*LSTAADMWGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 590)LSWAADMWGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 591)*LSWAADMWGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 592)LSTAADLWGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 593)*LSTAADLWGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 594)LSWAADLGWVVWDWLASGLDKDYLKPDD (SEQ ID NO: 595)*LSWAADLGWVVWDWLASGLDKDYLKPDD (SEQ ID NO: 596)LSTAADVWGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 597)*LSTAADVWGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 598)LSWAADVWGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 599)*LSWAADVWGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 600)LSTAADMQGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 601)*LSTAADMQGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 602)LSWAADMQGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 603)*LSWAADMQGVVWDWLASGLDKDYLKPDD (SEQ ID NO: 604)LSTAADLQAVVWDWLASGLDKDYLKPDD (SEQ ID NO: 605)*LSTAADLQAVVWDWLASGLDKDYLKPDD (SEQ ID NO: 606)LSWAADLQAVVWDWLASGLDKDYLKPDD (SEQ ID NO: 607)*LSWAADLQAVVWDWLASGLDKDYLKPDD (SEQ ID NO: 608)LSTAADVQAVVWDWLASGLDKDYLKPDD (SEQ ID NO: 609)*LSTAADVQAVVWDWLASGLDKDYLKPDD (SEQ ID NO: 610)LSWAADVQAVVWDWLASGLDKDYLKPDD (SEQ ID NO: 611)*LSWAADVQAVVWDWLASGLDKDYLKPDD (SEQ ID NO: 612)LSTAADMWAVVWDWLASGLDKDYLKPDD (SEQ ID NO: 613)*LSTAADMWAVVWDWLASGLDKDYLKPDD (SEQ ID NO: 614)LSWAADMWAVVWDWLASGLDKDYLKPDD (SEQ ID NO: 615)*LSWAADMWAVVWDWLASGLDKDYLKPDD (SEQ ID NO: 616)LSTAADLWAVVWDWLASGLDKDYLKPDD (SEQ ID NO: 617)*LSTAADLWAVVWDWLASGLDKDYLKPDD (SEQ ID NO: 618)LSWAADLWAVVWDWLASGLDKDYLKPDD (SEQ ID NO: 619)*LSWAADLWAVVWDWLASGLDKDYLKPDD (SEQ ID NO: 620)LSTAADVWAVVWDWLASGLDKDYLKPDD (SEQ ID NO: 621)*LSTAADVWAVVWDWLASGLDKDYLKPDD (SEQ ID NO: 622)LSWAADVWAVVWDWLASGLDKDYLKPDD (SEQ ID NO: 623)*LSWAADVWAVVWDWLASGLDKDYLKPDD (SEQ ID NO: 624)LSTAADMQGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 625)*LSTAADMQGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 626)LSWAADMQGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 627)*LSWAADMQGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 628)LSTAADLQGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 629)*LSTAADLQGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 630)LSWAADLQGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 631)*LSWAADLQGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 632)LSTAADVQGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 633)*LSTAADVQGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 634)LSWAADVQGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 635)*LSWAADVQGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 636)LSTAADMWGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 637)*LSTAADMWGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 638)LSWAADMWGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 639)*LSWAADMWGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 640)LSTAADLWGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 641)*LSTAADLWGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 642)LSWAADLWGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 643)*LSWAADLWGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 644)LSTAADVWGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 645)*LSTAADVWGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 646)LSWAADVWGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 647)*LSWAADVWGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 648)LSTAADMQAVVTDGVASGLDKDYLKPDD (SEQ ID NO: 649)*LSTAADMQAVVTDGVASGLDKDYLKPDD (SEQ ID NO: 650)LSWAADMQAVVTDGVASGLDKDYLKPDD (SEQ ID NO: 651)*LSWAADMQAVVTDGVASGLDKDYLKPDD (SEQ ID NO: 652)LSTAADMQGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 653)*LSTAADMQGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 654)LSWAADMQGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 655)*LSWAADMQGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 656)LSTAADVQGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 657)*LSTAADVQGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 658)LSWAADVQGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 659)*LSWAADVQGVVTDGVASGLDKDYLKPDD (SEQ ID NO: 660)LSTAADMWAVVTDGVASGLDKDYLKPDD (SEQ ID NO: 661)*LSTAADMWAVVTDGVASGLDKDYLKPDD (SEQ ID NO: 662)LSWAADMWAVVTDGVASGLDKDYLKPDD (SEQ ID NO: 663)*LSWAADMWAVVTDGVASGLDKDYLKPDD (SEQ ID NO: 664)LSTAADLWAVVTDGVASGLDKDYLKPDD (SEQ ID NO: 665)*LSTAADLWAVVTDGVASGLDKDYLKPDD (SEQ ID NO: 666)LSWAADLWAVVTDGVASGLDKDYLKPDD (SEQ ID NO: 667)*LSWAADLWAVVTDGVASGLDKDYLKPDD (SEQ ID NO: 668)LSTAADVWAVVTDGVASGLDKDYLKPDD (SEQ ID NO: 669)*LSTAADVWAVVTDGVASGLDKDYLKPDD (SEQ ID NO: 670)LSWAADVWAVVTDGVASGLDKDYLKPDD (SEQ ID NO: 671)*LSWAADVWAVVTDGVASGLDKDYLKPDD (SEQ ID NO: 672)LSTAADMQGVVWDGVASGLDKDYLKPDD (SEQ ID NO: 673)*LSTAADMQGVVWDGVASGLDKDYLKPDD (SEQ ID NO: 674)LSWAADMQGVVWDGVASGLDKDYLKPDD (SEQ ID NO: 675)*LSWAADMQGVVWDGVASGLDKDYLKPDD (SEQ ID NO: 676)LSTAADLQGVVWDGVASGLDKDYLKPDD (SEQ ID NO: 677)*LSTAADLQGVVWDGVASGLDKDYLKPDD (SEQ ID NO: 678)LSWAADLQGVVWDGVASGLDKDYLKPDD (SEQ ID NO: 679)*LSWAADLQGVVWDGVASGLDKDYLKPDD (SEQ ID NO: 680)LSTAADVQGVVWDGVASGLDKDYLKPDD (SEQ ID NO: 681)*LSTAADVQGVVWDGVASGLDKDYLKPDD (SEQ ID NO: 682)LSWAADVQGVVWDGVASGLDKDYLKPDD (SEQ ID NO: 683)*LSWAADVQGVVWDGVASGLDKDYLKPDD (SEQ ID NO: 684)LSTAADMWGVVWDGVASGLDKDYLKPDD (SEQ ID NO: 685)*LSTAADMWGVVWDGVASGLDKDYLKPDD (SEQ ID NO: 686)LSWAADMWGVVWDGVASGLDKDYLKPDD (SEQ ID NO: 687)*LSWAADMWGVVWDGVASGLDKDYLKPDD (SEQ ID NO: 688)LSTAADLWGVVWDGVASGLDKDYLKPDD (SEQ ID NO: 689)*LSTAADLWGVVWDGVASGLDKDYLKPDD (SEQ ID NO: 690)LSWAADLWGVVWDGVASGLDKDYLKPDD (SEQ ID NO: 691)*LSWAADLWGVVWDGVASGLDKDYLKPDD (SEQ ID NO: 692)LSTAADVWGVVWDGVASGLDKDYLKPDD (SEQ ID NO: 693)*LSTAADVWGVVWDGVASGLDKDYLKPDD (SEQ ID NO: 694)LSWAADVWGVVWDGVASGLDKDYLKPDD (SEQ ID NO: 695)*LSWAADVWGVVWDGVASGLDKDYLKPDD (SEQ ID NO: 696)LSTAADMQAVVWDGVASGLDKDYLKPDD (SEQ ID NO: 697)*LSTAADMQAVVWDGVASGLDKDYLKPDD (SEQ ID NO: 698)LSWAADMQAVVWDGVASGLDKDYLKPDD (SEQ ID NO: 699)*LSWAADMQAVVWDGVASGLDKDYLKPDD (SEQ ID NO: 700)LSTAADLQAVVWDGVASGLDKDYLKPDD (SEQ ID NO: 701)*LSTAADLQAVVWDGVASGLDKDYLKPDD (SEQ ID NO: 702)LSWAADLQAVVWDGVASGLDKDYLKPDD (SEQ ID NO: 703)*LSWAADLQAVVWDGVASGLDKDYLKPDD (SEQ ID NO: 704)LSTAADVQAVVWDGVASGLDKDYLKPDD (SEQ ID NO: 705)*LSTAADVQAVVWDGVASGLDKDYLKPDD (SEQ ID NO: 706)LSWAADVQAVVWDGVASGLDKDYLKPDD (SEQ ID NO: 707)*LSWAADVQAVVWDGVASGLDKDYLKPDD (SEQ ID NO: 708)LSTAADMWAVVWDGVASGLDKDYLKPDD (SEQ ID NO: 709)*LSTAADMWAVVWDGVASGLDKDYLKPDD (SEQ ID NO: 710)LSWAADMWAVVWDGVASGLDKDYLKPDD (SEQ ID NO: 711)*LSWAADMWAVVWDGVASGLDKDYLKPDD (SEQ ID NO: 712)LSTAADLWAVVWDGVASGLDKDYLKPDD (SEQ ID NO: 713)*LSTAADLWAVVWDGVASGLDKDYLKPDD (SEQ ID NO: 714)LSWAADLWAVVWDGVASGLDKDYLKPDD (SEQ ID NO: 715)*LSWAADLWAVVWDGVASGLDKDYLKPDD (SEQ ID NO: 716)LSTAADVWAVVWDGVASGLDKDYLKPDD (SEQ ID NO: 717)*LSTAADVWAVVWDGVASGLDKDYLKPDD (SEQ ID NO: 718)LSWAADVWAVVWDGVASGLDKDYLKPDD (SEQ ID NO: 719)*LSWAADVWAVVWDGVASGLDKDYLKPDD (SEQ ID NO: 720)LSTAADMQGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 721)*LSTAADMQGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 722)LSWAADMQGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 723)*LSWAADMQGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 724)LSTAADLQGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 725)*LSTAADLQGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 726)LSWAADLQGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 727)*LSWAADLQGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 728)LSTAADVQGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 729)*LSTAADVQGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 730)LSWAADVQGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 731)*LSWAADVQGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 732)LSTAADMWGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 733)*LSTAADMWGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 734)LSWAADMWGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 735)*LSWAADMWGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 736)LSTAADLWGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 737)*LSTAADLWGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 738)LSWAADLWGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 739)*LSWAADLWGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 740)LSTAADVWGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 741)*LSTAADVWGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 742)LSWAADVWGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 743)*LSWAADVWGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 744)LSTAADMQGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 745)*LSTAADMQGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 746)LSWAADMQGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 747)*LSWAADMQGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 748)LSTAADLQGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 749)*LSTAADLQGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 750)LSWAADLQGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 751)*LSWAAD:QGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 752)LSTAADVQGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 753)*LSTAADVQGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 754)LSWAADVQGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 755)*LSWAADVQGVVTDTVASGLDKDYLKPDD (SEQ ID NO: 756)LSTAADMWAVVTDTVASGLDKDYLKPDD (SEQ ID NO: 757)*LSTAADMWAVVTDTVASGLDKDYLKPDD (SEQ ID NO: 758)LSWAADMWAVVTDTVASGLDKDYLKPDD (SEQ ID NO: 759)*LSWAADMWAVVTDTVASGLDKDYLKPDD (SEQ ID NO: 760)LSTAADLWAVVTDTVASGLDKDYLKPDD (SEQ ID NO: 761)*LSTAADLWAVVTDTVASGLDKDYLKPDD (SEQ ID NO: 762)LSWAADLWAVVTDTVASGLDKDYLKPDD (SEQ ID NO: 763)*LSWAADLWAVVTDTVASGLDKDYLKPDD (SEQ ID NO: 764)LSTAADVWAVVTDTVASGLDKDYLKPDD (SEQ ID NO: 765)*LSTAADVWAVVTDTVASGLDKDYLKPDD (SEQ ID NO: 766)LSWAADVWAVVTDTVASGLDKDYLKPDD (SEQ ID NO: 767)*LSWAADVWAVVTDTVASGLDKDYLKPDD (SEQ ID NO: 768)LSTAADMQGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 769)*LSTAADMQGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 770)LSWAADMQGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 771)*LSWAADMQGVVWTGVASGLDKDYLKPDD (SEQ ID NO: 772)LSTAADLQGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 773)*LSTAADLQGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 774)LSWAADLQGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 775)*LSWAADLQGVVWDTASGLDKDYLKPDD (SEQ ID NO: 776)LSTAADVQGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 777)*LSTAADVQGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 778)LSWAADVQGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 779)*LSWAADVQGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 780)LSTAADMWGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 781)*LSTAADMWGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 782)LSWAADMWGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 783)*LSWAADMWGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 784)LSTAADLWGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 785)*LSTAADLWGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 786)LSWAADLWGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 787)*LSWAADLWGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 788)LSTAADVWGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 789)*LSTAADVWGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 790)LSWAADVWGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 791)*LSWAADVWGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 792)LSTAADMQGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 793)*LSTAADMQGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 794)LSWAADMQGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 795)*LSWAADMQGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 796)LSTAADLQGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 797)*LSTAADLQGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 798)LSWAADLQGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 799)*LSWAADLQGVVWDTVASGLDKDYLKPDD (SEQ ID NO: 800)LSTAADVQAVVWDTVASGLDKDYLKPDD (SEQ ID NO: 801)*LSTAADVQAVVWDTVASGLDKDYLKPDD (SEQ ID NO: 802)LSWAADVQAVVWDTVASGLDKDYLKPDD (SEQ ID NO: 803)*LSWAADVQAVVWDTVASGLDKDYLKPDD (SEQ ID NO: 804)LSTAADMWAVVWDTVASGLDKDYLKPDD (SEQ ID NO: 805)*LSTAADMWAVVWDTVASGLDKDYLKPDD (SEQ ID NO: 806)LSWAADMWAVVWDTVASGLDKDYLKPDD (SEQ ID NO: 807)*LSWAADMWAVVWDTVASGLDKDYLKPDD (SEQ ID NO: 808)LSTAADLWAVVWDTVASGLDKDYLKPDD (SEQ ID NO: 809)*LSTAADLWAVVWDTVASGLDKDYLKPDD (SEQ ID NO: 810)LSWAADLWAVVWDTVASGLDKDYLKPDD (SEQ ID NO: 811)*LSWAADLWAVVWDTVASGLDKDYLKPDD (SEQ ID NO: 812)LSTAADVWAVVWDTVASGLDKDYLKPDD (SEQ ID NO: 813)*LSTAADVWAVVWDTVASGLDKDYLKPDD (SEQ ID NO: 814)LSWAADVWAVVWDTVASGLDKDYLKPDD (SEQ ID NO: 815)*LSWAADVWAVVWDTVASGLDKDYLKPDD (SEQ ID NO: 816)LSTAADMQGVVTDWVASGLDKDYLKPDD (SEQ ID NO: 817)*LSTAADMQGVVTDWVASGLDKDYLKPDD (SEQ ID NO: 818)LSWAADMQGVVTDWVASGLDKDYLKPDD (SEQ ID NO: 819)*LSWAADMQGVVTDWVASGLDKDYLKPDD (SEQ ID NO: 820)LSTAADLQGVVTDWVASGLDKDYLKPDD (SEQ ID NO: 821)*LSTAADLQGVVTDWVASGLDKDYLKPDD (SEQ ID NO: 822)LSWAADLQGVVTDWVASGLDKDYLKPDD (SEQ ID NO: 823)*LSWAADLQGVVTDWVASGLDKDYLKPDD (SEQ ID NO: 824)LSTAADVQGVVTDWVASGLDKDYLKPDD (SEQ ID NO: 825)*LSTAADVQGVVTDWVASGLDKDYLKPDD (SEQ ID NO: 826)LSWAADVQGVVTDWVASGLDKDYLKPDD (SEQ ID NO: 827)*LSWAADVQGVVTDWVASGLDKDYLKPDD (SEQ ID NO: 828)LSTAADMWGVVTDWVASGLDKDYLKPDD (SEQ ID NO: 829)*LSTAADMWGVVTDWVASGLDKDYLKPDD (SEQ ID NO: 830)LSWAADMWGVVTDWVASGLDKDYLKPDD (SEQ ID NO: 831)*LSWAADMWGVVTDWVASGLDKDYLKPDD (SEQ ID NO: 832)LSTAADLWGVVTDWVASGLDKDYLKPDD (SEQ ID NO: 833)*LSTAADLWGVVTDWVASGLDKDYLKPDD (SEQ ID NO: 834)LSWAADLWGVVTDWVASGLDKDYLKPDD (SEQ ID NO: 835)*LSWAADLWGVVTDWVASGLDKDYLKPDD (SEQ ID NO: 836)LSTAADVWGVVTDWVASGLDKDYLKPDD (SEQ ID NO: 837)*LSTAADVWGVVTDWVASGLDKDYLKPDD (SEQ ID NO: 838)LSWAADVWGVVTDWVASGLDKDYLKPDD (SEQ ID NO: 839)*LSWAADVWGVVTDWVASGLDKDYLKPDD (SEQ ID NO: 840)LSTAADMQAVVTDWVASGLDKDYLKPDD (SEQ ID NO: 841)*LSTAADMQAVVTDWVASGLDKDYLKPDD (SEQ ID NO: 842)LSWAADMQAVVTDWVASGLDKDYLKPDD (SEQ ID NO: 843)*LSWAADMQAVVTDWVASGLDKDYLKPDD (SEQ ID NO: 844)LSTAADLQAVVTDWVASGLDKDYLKPDD (SEQ ID NO: 845)*LSTAADLQAVVTDWVASGLDKDYLKPDD (SEQ ID NO: 846)LSWAADLQAVVTDWVASGLDKDYLKPDD (SEQ ID NO: 847)*LSWAADLQAVVTDWVASGLDKDYLKPDD (SEQ ID NO: 848)LSTAADVQAVVTDWVASGLDKDYLKPDD (SEQ ID NO: 849)*LSTAADVQAVVTDWVASGLDKDYLKPDD (SEQ ID NO: 850)LSWAADVQAVVTDWVASGLDKDYLKPDD (SEQ ID NO: 851)*LSWAADVQAVVTDWVASGLDKDYLKPDD (SEQ ID NO: 852)LSTAADMWAVVTDWVASGLDKDYLKPDD (SEQ ID NO: 853)*LSTAADMWAVVTDWVASGLDKDYLKPDD (SEQ ID NO: 854)LSWAADMWAVVTDWVASGLDKDYLKPDD (SEQ ID NO: 855)*LSWAADMWAVVTDWVASGLDKDYLKPDD (SEQ ID NO: 856)LSTAADLWAVVTDWVASGLDKDYLKPDD (SEQ ID NO: 857)*LSTAADLWAVVTDWVASGLDKDYLKPDD (SEQ ID NO: 858)LSWAADLWAVVTDWVASGLDKDYLKPDD (SEQ ID NO: 859)*LSWAADLWAVVTDWVASGLDKDYLKPDD (SEQ ID NO: 860)LSTAADVWAVVTDWVASGLDKDYLKPDD (SEQ ID NO: 861)*LSTAADVWAVVTDWVASGLDKDYLKPDD (SEQ ID NO: 862)LSWAADVWAVVTDWVASGLDKDYLKPDD (SEQ ID NO: 863)*LSWAADVWAVVTDWVASGLDKDYLKPDD (SEQ ID NO: 864)LSTAADMQGVVWDWVASGLDKDYLKPDD (SEQ ID NO: 865)*LSTAADMQGVVWDWVASGLDKDYLKPDD (SEQ ID NO: 866)LSWAADMQGVVWDWVASGLDKDYLKPDD (SEQ ID NO: 867)*LSWAADMQGVVWDWVASGLDKDYLKPDD (SEQ ID NO: 868)LSTAADLQGVVWDWVASGLDKDYLKPDD (SEQ ID NO: 869)*LSTAADLQGVVWDWVASGLDKDYLKPDD (SEQ ID NO: 870)LSWAADLQGVVWDWVASGLDKDYLKPDD (SEQ ID NO: 871)*LSWAADLQGVVWDWVASGLDKDYLKPDD (SEQ ID NO: 872)LSTAADVQGVVWDWVASGLDKDYLKPDD (SEQ ID NO: 873)*LSTAADVQGVVWDWVASGLDKDYLKPDD (SEQ ID NO: 874)LSWAADVQGVVWDWVASGLDKDYLKPDD (SEQ ID NO: 875)*LSWAADVQGVVWDWVASGLDKDYLKPDD (SEQ ID NO: 876)LSTAADMWGVVWDWVASGLDKDYLKPDD (SEQ ID NO: 877)*LSTAADMWGVVWDWVASGLDKDYLKPDD (SEQ ID NO: 878)LSWAADMWGVVWDWVASGLDKDYLKPDD (SEQ ID NO: 879)*LSWAADMWGVVWDWVASGLDKDYLKPDD (SEQ ID NO: 880)LSTAADLWGVVWDWVASGLDKDYLKPDD (SEQ ID NO: 881)*LSTAADLWGVVWDWVASGLDKDYLKPDD (SEQ ID NO: 882)LSWAADLWGVVWDWVASGLDKDYLKPDD (SEQ ID NO: 883)*LSWAADLWGVVWDWVASGLDKDYLKPDD (SEQ ID NO: 884)LSTAADVWGVVWDWVASGLDKDYLKPDD (SEQ ID NO: 885)*LSTAADVWGVVWDWVASGLDKDYLKPDD (SEQ ID NO: 886)LSWAADVWGVVWDWVASGLDKDYLKPDD (SEQ ID NO: 887)*LSWAADVWGVVWDWVASGLDKDYLKPDD (SEQ ID NO: 888)LSTAADMQAVVWDWVASGLDKDYLKPDD (SEQ ID NO: 889)*LSTAADMQAVVWDWVASGLDKDYLKPDD (SEQ ID NO: 890)LSWAADMQAVVWDWVASGLDKDYLKPDD (SEQ ID NO: 891)*LSWAADMQAVVWDWVASGLDKDYLKPDD (SEQ ID NO: 892)LSTAADLQAVVWDWVASGLDKDYLKPDD (SEQ ID NO: 893)*LSTAADLQAVVWDWVASGLDKDYLKPDD (SEQ ID NO: 894)LSWAADLQAVVWDWVASGLDKDYLKPDD (SEQ ID NO: 895)*LSWAADLQAVVWDWVASGLDKDYLKPDD (SEQ ID NO: 896)LSTAADVQAVVWDWVASGLDKDYLKPDD (SEQ ID NO: 897)*LSTAADVQAVVWDWVASGLDKDYLKPDD (SEQ ID NO: 898)LSWAADVQAVVWDWVASGLDKDYLKPDD (SEQ ID NO: 899)*LSWAADVQAVVWDWVASGLDKDYLKPDD (SEQ ID NO: 900)LSTAADMWAVVWDWVASGLDKDYLKPDD (SEQ ID NO: 901)*LSTAADMWAVVWDWVASGLDKDYLKPDD (SEQ ID NO: 902)LSWAADMWAVVWDWVASGLDKDYLKPDD (SEQ ID NO: 903)*LSWAADMWAVVWDWVASGLDKDYLKPDD (SEQ ID NO: 904)LSTAADLWAVVWDWVASGLDKDYLKPDD (SEQ ID NO: 905)*LSTAADLWAVVWDWVASGLDKDYLKPDD (SEQ ID NO: 906)LSWAADLWAVVWDWVASGLDKDYLKPDD (SEQ ID NO: 907)*LSWAADLWAVVWDWVASGLDKDYLKPDD (SEQ ID NO: 908)LSTAADVWAVVWDWVASGLDKDYLKPDD (SEQ ID NO: 909)*LSTAADVWAVVWDWVASGLDKDYLKPDD (SEQ ID NO: 910)LSWAADVWAVVWDWVASGLDKDYLKPDD (SEQ ID NO: 911)*LSWAADVWAVVWDWVASGLDKDYLKPDD (SEQ ID NO: 912)LSTAADMQGVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 913)*LSTAADMQGVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 914)LSWAADMQGVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 915)*LSWAADMQGVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 916)LSTAADLQGVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 917)*LSTAADLQGVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 918)LSWAADLQGVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 919)*LSWAADLQGVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 920)LSTAADVQGVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 921)*LSTAADVQGVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 922)LSWAADVQGVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 923)*LSWAADVQGVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 924)LSTAADMWGVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 925)*LSTAADMWGVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 926)LSWAADMWGVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 927)*LSWAADMWGVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 928)LSTAADLWGVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 929)*LSTAADLWGVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 930)LSWAADLWGVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 931)*LSWAADLWGVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 932)LSTAADVWGVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 933)*LSTAADVWGVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 934)LSWAADVWGVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 935)*LSWAADVWGVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 936)LSTAADMQAVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 937)*LSTAADMQAVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 938)LSWAADMQAVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 939)*LSWAADMQAVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 940)LSTAADLQAVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 941)*LSTAADLQAVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 942)LSWAADLQAVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 943)*LSWAADLQAVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 944)LSTAADVQAVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 945)*LSTAADVQAVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 946)LSWAADVQAVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 947)*LSWAADVQAVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 948)LSTAADMWAVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 949)*LSTAADMWAVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 950)LSWAADMWAVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 951)*LSWAADMWAVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 952)LSTAADLWAVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 953)*LSTAADLWAVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 954)LSWAADLWAVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 955)*LSWAADLWAVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 956)LSTAADVWAVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 957)*LSTAADVWAVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 958)LSWAADVWAVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 959)*LSWAADVWAVVTDGMASGLDKDYLKPDD$ (SEQ ID NO: 960)LSTAADMQGVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 961)*LSTAADMQGVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 962)LSWAADMQGVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 963)*LSWAADMQGVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 964)LSTAADLQGVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 965)*LSTAADLQGVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 966)LSWAADLQGVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 967)*LSWAADLQGVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 968)LSTAADVQGVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 969)*LSTAADVQGVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 970)LSWAADVQGVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 971)*LSWAADVQGVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 972)LSTAADMWGVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 973)*LSTAADMWGVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 974)LSWAADMWGVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 975)*LSWAADMWGVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 976)LSTAADLWGVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 977)*LSTAADLWGVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 978)LSWAADLWGVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 979)*LSWAADLWGVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 980)LSTAADVWGVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 981)*LSTAADVWGVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 982)LSWAADVWGVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 983)*LSWAADVWGVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 984)LSTAADMQAVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 985)*LSTAADMQAVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 986)LSWAADMQAVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 987)*LSWAADMQAVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 988)LSTAADLQAVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 989)*LSTAADLQAVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 990)LSWAADLQAVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 991)*LSWAADLQAVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 992)LSTAADVQAVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 993)*LSTAADVQAVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 994)LSWAADVQAVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 995)*LSWAADVQAVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 996)LSTAADMWAVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 997)*LSTAADMWAVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 998)LSWAADMWAVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 999)*LSWAADMWAVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 1000)LSTAADLWAVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 1001)*LSTAADLWAVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 1002)LSWAADLWAVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 1003)*LSWAADLWAVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 1004)LSTAADVWAVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 1005)*LSTAADVWAVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 1006)LSWAADVWAVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 1007)*LSWAADVWAVVWDGMASGLDKDYLKPDD$ (SEQ ID NO: 1008)LSTAADMQGVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1009)*LSTAADMQGVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1010)LSWAADMQGVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1011)*LSWAADMQGVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1012)LSTAADLQGVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1013)*LSTAADLQGVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1014)LSWAADLQGVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1015)*LSWAADLQGVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1016)LSTAADVQGVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1017)*LSTAADVQGVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1018)LSWAADVQGVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1019)*LSWAADVQGVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1020)LSTAADMWGVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1021)*LSTAADMWGVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1022)LSWAADMWGVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1023)*LSWAADMWGVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1024)LSTAADLWGVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1025)*LSTAADLWGVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1026)LSWAADLWGVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1027)*LSWAADLQGVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1028)LSTAADVWGVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1029)*LSTAADVWGVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1030)LSWAADVWGVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1031)*LSWAADVWGVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1032)LSTAADMQAVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1033)*LSTAADMQAVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1034)LSWAADMQAVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1035)*LSWAADMQAVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1036)LSTAADLQAVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1037)*LSTAADLQAVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1038)LSWAADLQAVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1039)*LSWAADLQAVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1040)LSTAADVQAVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1041)*LSTAADVQAVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1042)LSWAADVQAVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1043)*LSWAADVQAVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1044)LSTAADMWAVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1045)*LSTAADMWAVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1046)LSWAADMWAVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1047)*LSWAADMWAVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1048)LSTAADLWAVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1049)*LSTAADLWAVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1050)LSWAADLWAVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1051)*LSWAADLWAVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1052)LSTAADVWAVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1053)*LSTAADVWAVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1054)LSWAADVWAVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1055)*LSWAADVWAVVTDTMASGLDKDYLKPDD$ (SEQ ID NO: 1056)LSTAADMQGVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1057)*LSTAADMQGVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1058)LSWAADMQGVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1059)*LSWAADMQGVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1060)LSTAADLQGVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1061)*LSTAADLQGVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1062)LSWAADLQGVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1063)*LSWAADLQGVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1064)LSTAADVQGVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1065)*LSTAADVQGVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1066)LSWAADVQGVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1067)*LSWAADVQGVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1068)LSTAADMWGVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1069)*LSTAADMWGVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1070)LSWAADMWGVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1071)*LSWAADMWGVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1072)LSTAADLWGVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1073)*LSTAADLWGVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1074)LSWAADLWGVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1075)*LSWAADLWGVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1076)LSTAADVWGVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1077)*LSTAADVWGVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1078)LSWAADVWGVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1079)*LSWAADVWGVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1080)LSTAADMQAVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1081)*LSTAADMQAVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1082)LSWAADMQAVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1083)*LSWAADMQAVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1084)LSTAADLQAVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1085)*LSTAADLQAVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1086)LSWAADLQAVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1087)*LSWAADLQAVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1088)LSTAADVQAVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1089)*LSTAADVQAVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1090)LSWAADVQAVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1091)*LSWAADVQAVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1092)LSTAADMWAVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1093)*LSTAADMWAVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1094)LSWAADMWAVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1095)*LSWAADMWAVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1096)LSTAADLWAVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1097)*LSTAADLWAVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1098)LSWAADLWAVVWDGTMSGLDKDYLKPDD$ (SEQ ID NO: 1099)*LSWAADLWAVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1100)LSTAADVWAVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1101)*LSTAADVWAVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1102)LSWAADVWAVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1103)*LSWAADVWAVVWDTMASGLDKDYLKPDD$ (SEQ ID NO: 1104)LSTAADMQGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1105)*LSTAADMQGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1106)LSWAADMQGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1107)*LSWAADMQGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1108)LSTAADLQGVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1109)*LSTAADLQGVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1110)LSWAADLQGVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1111)*LSWAADLQGVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1112)LSTAADVQGVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1113)*LSTAADVQGVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1114)LSWAADVQGVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1115)*LSWAADVQGVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1116)LSTAADMWGVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1117)*LSTAADMWGVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1118)LSWAADMWGVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1119)*LSWAADMWGVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1120)LSTAADLWGVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1121)*LSTAADLWGVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1122)LSWAADLWGVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1123)*LSWAADLWGVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1124)LSTAADVWGVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1125)*LSTAADVWGVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1126)LSWAADVWGVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1127)*LSWAADVWGVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1128)LSTAADMQGVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1129)*LSTAADMQGVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1130)LSWAADMQGVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1131)*LSWAADMQGVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1132)LSTAADLQAVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1133)*LSTAADLQAVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1134)LSWAADLQAVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1135)*LSWAADLQAVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1136)LSTAADVQAVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1137)*LSTAADVQAVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1138)LSWAADVQAVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1139)*LSWAADVQAVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1140)LSTAADMWAVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1141)*LSTAADMWAVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1142)LSWAADMWAVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1143)*LSWAADMWAVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1144)LSTAADLWAVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1145)*LSTAADLWAVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1146)LSWAADLWAVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1147)*LSWAADLWAVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1148)LSTAADVWAVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1149)*LSTAADVWAVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1150)LSWAADVWAVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1151)*LSWAADVWAVVTDWMASGLDKDYLKPDD$ (SEQ ID NO: 1152)LSTAADMQGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1153)*LSTAADMQGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1154)LSWAADMQGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1155)*LSWAADMQGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1156)LSTAADLQGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1157)*LSTAADLQGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1158)LSWAADLQGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1159)*LSWAADLQGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1160)LSTAADVQGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1161)*LSTAADVQGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1162)LSWAADVQGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1163)*LSWAADVQGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1164)LSTAADMWGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1165)*LSTAADMWGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1166)LSWAADMWGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1167)*LSWAADMWGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1168)LSTAADLWGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1169)*LSTAADLWGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1170)LSWAADLWGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1171)*LSWAADLWGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1172)LSTAADVWGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1173)*LSTAADVWGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1174)LSWAADVWGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1175)*LSWAADVWGVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1176)LSTAADMQAVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1177)*LSTAADMQAVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1178)LSWAADMQAVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1179)*LSWAADMQAVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1180)LSTAADLQAVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1181)*LSTAADLQAVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1182)LSWAADLQAVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1183)*LSWAADLQAVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1184)LSTAADVQAVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1185)*LSTAADVQAVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1186)LSWAADVQAVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1187)*LSWAADVQAVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1188)LSTAADMWAVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1189)*LSTAADMWAVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1190)LSWAADMWAVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1191)*LSWAADMWAVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1192)LSTAADLWAVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1193)*LSTAADLWAVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1194)LSWAADLWAVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1195)*LSWAADLWAVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1196)LSTAADVWAVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1197)*LSTAADVWAVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1198)LSWAADVWAVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1199)*LSWAADVWAVVWDWMASGLDKDYLKPDD$ (SEQ ID NO: 1200)LSTAADMQGVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1201)*LSTAADMQGVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1202)LSWAADMQGVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1203)*LSWAADMQGVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1204)LSTAADLQGVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1205)*LSTAADLQGVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1206)LSWAADLQGVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1207)*LSWAADLQGVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1208)LSTAADVQGVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1209)*LSTAADVQGVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1210)LSWAADVQGVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1211)*LSWAADVQGVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1212)LSTAADMWGVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1213)*LSTAADMWGVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1214)LSWAADMWGVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1215)*LSWAADMWGVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1216)LSTAADLWGVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1217)*LSTAADLWGVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1218)LSWAADLWGVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1219)*LSWAADLWGVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1220)LSTAADVWGVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1221)*LSTAADVWGVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1222)LSWAADVWGVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1223)*LSWAADVWGVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1224)LSTAADMQAVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1225)*LSTAADMQAVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1226)LSWAADMQAVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1227)*LSWAADMQAVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1228)LSTAADLQAVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1229)*LSTAADLQAVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1230)LSWAADLQAVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1231)*LSWAADLQAVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1232)LSTAADVQAVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1233)*LSTAADVQAVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1234)LSWAADVQAVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1235)*LSWAADVQAVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1236)LSTAADMWAVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1237)*LSTAADMWAVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1238)LSWAADMWAVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1239)*LSWAADMWAVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1240)LSTAADLWAVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1241)*LSTAADLWAVVTDGLVASGLDKDYLKPDD$ (SEQ ID NO: 1242)LSWAADLWAVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1243)*LSWAADLWAVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1244)LSTAADVWAVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1245)*LSTAADVWAVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1246)LSWAADVWAVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1247)*LSWAADVWAVVTDGLASGLDKDYLKPDD$ (SEQ ID NO: 1248)LSTAADMQGVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1249)*LSTAADMQGVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1250)LSWAADMQGVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1251)*LSWAADMQGVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1252)LSTAADLQGVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1253)*LSTAADLQGVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1254)LSWAADLQGVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1255)*LSWAADLQGVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1256)LSTAADVQGVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1257)*LSTAADVQGVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1258)LSWAADVQGVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1259)*LSWAADVQGVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1260)LSTAADMWGVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1261)*LSTAADMWGVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1262)LSWAADMWGVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1263)*LSWAADMWGVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1264)LSTAADLWGVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1265)*LSTAADLWGVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1266)LSWAADLWGVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1267)*LSWAADLWGVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1268)LSTAADVWGVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1269)*LSTAADVWGVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1270)LSWAADVWGVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1271)*LSWAADVWGVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1272)LSTAADMQAVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1273)*LSTAADMQAVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1274)LSWAADMQAVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1275)*LSWAADMQAVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1276)LSTAADLQAVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1277)*LSTAADLQAVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1278)LSWAADLQAVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1279)*LSWAADLQAVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1280)LSTAADVQAVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1281)*LSTAADVQAVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1282)LSWAADVQAVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1283)*LSWAADVQAVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1284)LSTAADMWAVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1285)*LSTAADMWAVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1286)LSWAADMWAVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1287)*LSWAADMWAVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1288)LSTAADLWAVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1289)*LSTAADLWAVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1290)LSWAADLWAVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1291)*LSWAADLWAVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1292)LSTAADVWAVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1293)*LSTAADVWAVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1294)LSWAADVWAVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1295)*LSWAADVWAVVWDGLASGLDKDYLKPDD$ (SEQ ID NO: 1296)LSTAADMQGVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1297)*LSTAADMQGVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1298)LSWAADMQGVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1299)*LSWAADMQGVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1300)LSTAADLQGVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1301)*LSTAADLQGVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1302)LSWAADLQGVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1303)*LSWAADLQGVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1304)LSTAADVQGVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1305)*LSTAADVQGVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1306)LSWAADVQGVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1307)*LSWAADVQGVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1308)LSTAADMWGVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1309)*LSTAADMWGVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1310)LSWAADMWGVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1311)*LSWAADMWGVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1312)LSTAADLWGVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1313)*LSTAADLWGVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1314)LSWAADLWGVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1315)*LSWAADLWGVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1316)LSTAADVWGVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1317)*LSTAADVWGVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1318)LSWAADVWGVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1319)*LSWAADVWGVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1320)LSTAADMQAVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1321)*LSTAADMQAVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1322)LSWAADMQAVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1323)*LSWAADMQAVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1324)LSTAADLQAVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1325)*LSTAADLQAVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1326)LSWAADLQAVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1327)*LSWAADLQAVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1328)LSTAADVQAVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1329)*LSTAADVQAVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1330)LSWAADVQAVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1331)*LSWAADVQAVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1332)LSTAADMWAVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1333)*LSTAADMWAVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1334)LSWAADMWAVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1335)*LSWAADMWAVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1336)LSTAADLWAVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1337)*LSTAADLWAVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1338)LSWAADLWAVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1339)*LSWAADLWAVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1340)LSTAADVWAVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1341)*LSTAADVWAVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1342)LSWAADVWAVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1343)*LSWAADVWAVVTDTLASGLDKDYLKPDD$ (SEQ ID NO: 1344)LSTAADMQGVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1345)*LSTAADMQGVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1346)LSWAADMQGVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1347)*LSWAADMQGVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1348)LSTAADLQGVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1349)*LSTAADLQGVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1350)LSWAADLQGVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1351)*LSWAADLQGVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1352)LSTAADVQGVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1353)*LSTAADVQGVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1354)LSWAADVQGVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1355)*LSWAADVQGVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1356)LSTAADMWGVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1357)*LSTAADMWGVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1358)LSWAADMWGVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1359)*LSWAADMWGVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1360)LSTAADLWGVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1361)*LSTAADLWGVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1362)LSWAADLWGVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1363)*LSWAADLWGVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1364)LSTAADVWGVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1365)*LSTAADVWGVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1366)LSWAADVWGVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1367)*LSWAADVWGVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1368)LSTAADMQAVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1369)*LSTAADMQAVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1370)LSWAADMQAVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1371)*LSWAADMQAVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1372)LSTAADLQAVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1373)*LSTAADLQAVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1374)LSWAADLQAVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1375)*LSWAADLQAVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1376)LSTAADVQAVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1377)*LSTAADVQAVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1378)LSWAADVQAVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1379)*LSWAADVQAVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1380)LSTAADMWAVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1381)*LSTAADMWAVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1382)LSWAADMWAVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1383)*LSWAADMWAVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1384)LSTAADLWAVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1385)*LSTAADLWAVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1386)LSWAADLWAVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1387)*LSWAADLWAVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1388)LSTAADVWAVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1389)*LSTAADVWAVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1390)LSWAADVWAVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1391)*LSWAADVWAVVWDTLASGLDKDYLKPDD$ (SEQ ID NO: 1392)LSTAADMQGVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1393)*LSTAADMQGVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1394)LSWAADMQGVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1395)*LSWAADMQGVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1396)LSTAADLQGVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1397)*LSTAADLQGVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1398)LSWAADLQGVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1399)*LSWAADLQGVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1400)LSTAADVQGVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1401)*LSTAADVQGVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1402)LSWAADVQGVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1403)*LSWAADVQGVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1404)LSTAADMWGVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1405)*LSTAADMWGVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1406)LSWAADMWGVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1407)*LSWAADMWGVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1408)LSTAADLWGVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1409)*LSTAADLWGVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1410)LSWAADLWGVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1411)*LSWAADLWGVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1412)LSTAADVWGVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1413)*LSTAADVWGVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1414)LSWAADVWGVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1415)*LSWAADVWGVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1416)LSTAADMQAVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1417)*LSTAADMQAVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1418)LSWAADMQAVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1419)*LSWAADMQAVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1420)LSTAADLQAVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1421)*LSTAADLQAVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1422)LSWAADLQAVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1423)*LSWAADLQAVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1424)LSTAADVQAVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1425)*LSTAADVQAVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1426)LSWAADVQAVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1427)*LSWAADVQAVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1428)LSTAADMWAVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1429)*LSTAADMWAVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1430)LSWAADMWAVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1431)*LSWAADMWAVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1432)LSTAADLWAVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1433)*LSTAADLWAVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1434)LSWAADLWAVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1435)*LSWAADLWAVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1436)LSTAADVWAVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1437)*LSTAADVWAVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1438)LSWAADVWAVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1439)*LSWAADVWAVVTDWLASGLDKDYLKPDD$ (SEQ ID NO: 1440)LSTAADMQGVVWDWLASGLDKDYLKPDD$ (SEQ ID NO: 1441)*LSTAADMQGVVWDWLASGLDKDYLKPDD$ (SEQ ID NO: 1442)LSWAADMQGVVWDWLASGLDKDYLKPDD$ (SEQ ID NO: 1443)*LSWAADMQGVVWDWLASGLDKDYLKPDD$ (SEQ ID NO: 1444)LSTAADLQGVVWDWLASGLDKDYLKPDD$ (SEQ ID NO: 1445)*LSTAADLQGVVWDWLASGLDKDYLKPDD$ (SEQ ID NO: 1446)LSWAADLQGVVWDWLASGLDKDYLKPDD$ (SEQ ID NO: 1447)*LSWAADLQGVVWDWLASGLDKDYLKPDD$ (SEQ ID NO: 1448)LSTAADVQGVVWDWLASGLDKDYLKPDD$ (SEQ ID NO: 1449)*LSTAADVQGVVWDWLASGLDKDYLKPDD$ (SEQ ID NO: 1450)LSWAADVQGVVWDWLASGLDKDYLKPDD$ (SEQ ID NO: 1451)*LSWAADVQGVVWDWLASGLDKDYLKPDD$ (SEQ ID NO: 1452)LSTAADMWGVVWDWLASGLDKDYLKPDD$ (SEQ ID NO: 1453)*LSTAADMWGVVWDWLASGLDKDYLKPDD$ (SEQ ID NO: 1454)LSWAADMWGVVWDWLASGLDKDYLKPDD$ (SEQ ID NO: 1455)*LSWAADMWGVVWDWLASGLDKDYLKPDD$ (SEQ ID NO: 1456)LSTAADLWGVVWDWLASGLDKDYLKPDD$ (SEQ ID NO: 1457)*LSTAADLWGVVWDWLASGLDKDYLKPDD$ (SEQ ID NO: 1458)LSWAADLWGVVWDWLASGLDKDYLKPDD$ (SEQ ID NO: 1459)*LSWAADLWGVVWDWLASGLDKDYLKPDD$ (SEQ ID NO: 1460)LSTAADVWGVVWDWLASGLDKDYLKPDD$ (SEQ ID NO: 1461)*LSTAADVWGVVWDWLASGLDKDYLKPDD$ (SEQ ID NO: 1462)LSWAADVWGVVWDWLASGLDKDYLKPDD$ (SEQ ID NO: 1463)*LSWAADVWGVVWDWLASGLDKDYLKPDD$ (SEQ ID NO: 1464)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1465)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1466)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1467)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1468)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1469)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1470)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1471)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1472)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1473)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1474)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1475)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1476)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1477)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1478)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1479)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1480)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1481)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1482)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1483)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1484)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1485)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1486)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1487)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1488)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1489)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1490)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1491)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1492)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1493)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1494)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1495)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1496)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1497)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1498)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1499)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1500)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1501)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1502)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1503)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1504)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1505)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1506)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1507)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1508)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1509)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1510)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1511)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1512)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1513)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1514)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1515)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1516)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1517)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1518)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1519)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1520)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1521)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1522)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1523)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1524)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1525)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1526)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1527)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1528)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1529)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1530)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1531)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1532)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1533)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1534)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1535)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1536)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1537)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1538)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1539)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1540)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1541)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1542)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1543)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1544)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1545)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1546)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1547)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1548)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1549)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1550)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1551)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1552)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1553)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1554)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1555)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1556)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1557)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1558)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1559)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1560)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1561)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1562)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1563)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1564)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1565)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1566)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1567)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1568)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1569)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1570)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1571)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1572)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1573)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1574)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1575)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1576)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1577)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1578)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1579)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1580)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1581)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1582)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1583)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1584)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1585)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1586)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1587)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1588)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1589)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1590)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1591)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1592)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1593)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1594)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1595)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1596)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1597)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1598)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1599)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1600)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1601)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1602)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1603)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1604)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1605)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1606)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1607)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1608)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1609)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1610)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1611)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1612)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1613)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1614)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1615)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1616)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1617)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1618)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1619)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1620)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1621)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1622)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1623)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1624)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1625)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1626)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1627)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1628)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1629)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1630)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1631)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1632)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1633)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1634)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1635)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1636)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1637)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1638)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1639)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1640)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1641)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1642)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1643)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1644)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1645)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1646)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1647)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1648)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1649)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1650)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1651)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1652)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1653)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1654)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1655)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1656)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1657)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1658)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1659)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1660)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1661)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1662)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1663)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1664)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1665)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1666)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1667)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1668)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1669)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1670)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1671)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1672)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1673)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1674)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1675)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1676)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1677)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1678)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1679)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1680)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1681)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1682)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1683)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1684)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1685)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1686)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1687)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1688)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1689)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1690)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1691)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1692)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1693)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1694)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1695)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1696)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1697)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1698)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1699)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1700)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1701)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1702)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1703)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1704)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1705)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1706)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1707)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1708)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1709)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1710)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1711)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1712)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1713)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1714)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1715)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1716)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1717)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1718)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1719)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1720)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1721)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1722)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1723)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1724)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1725)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1726)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1727)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1728)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1729)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1730)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1731)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1732)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1733)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1734)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1735)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1736)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1737)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1738)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1739)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1740)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1741)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1742)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1743)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1744)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1745)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1746)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1747)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1748)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1749)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1750)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1751)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1752)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1753)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1754)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1755)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1756)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1757)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1758)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1759)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1760)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1761)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1762)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1763)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1764)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1765)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1766)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1767)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1768)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1769)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1770)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1771)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1772)LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1773)*LSTAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1774)LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1775)*LSWAADMQGVVWDGVASGLDKDYLKPDD$ (SEQ ID NO: 1776)*DDPKLYDKDLGSAVWDWVVAWVDAAWSL$ (SEQ ID NO: 1777)*DDPKLYDKDLGSAVWDWVVAWVDAAWSL (SEQ ID NO: 1778)*DDPKLYDKDLGSAVWDWVVAWVDAATSL$ (SEQ ID NO: 1779)*DDPKLYDKDLGSAVWDWVVAWVDAATSL (SEQ ID NO: 1780)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 1781)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 1782)*DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 1783)*DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 1784)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 1785)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 1786)*DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 1787)*DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 1788)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 1789)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 1790)*DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 1791)*DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 1792)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 1793)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 1794)*DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 1795)*DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 1796)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL$ (SEQ ID NO: 1797)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL (SEQ ID NO: 1798)*DDPKLYDKDLGSAVWDWVVAQMDAATSL$ (SEQ ID NO: 1799)*DDPKLYDKDLGSAVWDWVVAQMDAATSL (SEQ ID NO: 1800)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL$ (SEQ ID NO: 1801)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL (SEQ ID NO: 1802)*DDPKLYDKDLGSAVWDWVVGWVDAATSL$ (SEQ ID NO: 1803)*DDPKLYDKDLGSAVWDWVVGWVDAATSL (SEQ ID NO: 1804)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL$ (SEQ ID NO: 1805)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL (SEQ ID NO: 1806)*DDPKLYDKDLGSAVWDWVVGWLDAATSL$ (SEQ ID NO: 1807)*DDPKLYDKDLGSAVWDWVVGWLDAATSL (SEQ ID NO: 1808)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL$ (SEQ ID NO: 1809)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL (SEQ ID NO: 1810)*DDPKLYDKDLGSAVWDWVVGWMDAATSL$ (SEQ ID NO: 1811)*DDPKLYDKDLGSAVWDWVVGWMDAATSL (SEQ ID NO: 1812)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL$ (SEQ ID NO: 1813)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL (SEQ ID NO: 1814)*DDPKLYDKDLGSAVWDWVVGQVDAATSL$ (SEQ ID NO: 1815)*DDPKLYDKDLGSAVWDWVVGQVDAATSL (SEQ ID NO: 1816)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL$ (SEQ ID NO: 1817)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL (SEQ ID NO: 1818)*DDPKLYDKDLGSAVWDWVVGQLDAATSL$ (SEQ ID NO: 1819)*DDPKLYDKDLGSAVWDWVVGQLDAATSL (SEQ ID NO: 1820)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 1821)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 1822)*DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 1823)*DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 1824)*DDPKLYDKDLGSAVWDTVVAWVDAAWSL$ (SEQ ID NO: 1825)*DDPKLYDKDLGSAVWDTVVAWVDAAWSL (SEQ ID NO: 1826)*DDPKLYDKDLGSAVWDTVVAWVDAATSL$ (SEQ ID NO: 1827)*DDPKLYDKDLGSAVWDTVVAWVDAATSL (SEQ ID NO: 1828)*DDPKLYDKDLGSAVWDTVVAWLDAAWSL$ (SEQ ID NO: 1829)*DDPKLYDKDLGSAVWDTVVAWLDAAWSL (SEQ ID NO: 1830)*DDPKLYDKDLGSAVWDTVVAWLDAATSL$ (SEQ ID NO: 1831)*DDPKLYDKDLGSAVWDTVVAWLDAATSL (SEQ ID NO: 1832)*DDPKLYDKDLGSAVWDTVVAWMDAAWSL$ (SEQ ID NO: 1833)*DDPKLYDKDLGSAVWDTVVAWMDAAWSL (SEQ ID NO: 1834)*DDPKLYDKDLGSAVWDTVVAWMDAATSL$ (SEQ ID NO: 1835)*DDPKLYDKDLGSAVWDTVVAWMDAATSL (SEQ ID NO: 1836)*DDPKLYDKDLGSAVWDTVVAQVDAAWSL$ (SEQ ID NO: 1837)*DDPKLYDKDLGSAVWDTVVAQVDAAWSL (SEQ ID NO: 1838)*DDPKLYDKDLGSAVWDTVVAQVDAATSL$ (SEQ ID NO: 1839)*DDPKLYDKDLGSAVWDTVVAQVDAATSL (SEQ ID NO: 1840)*DDPKLYDKDLGSAVWDTVVAQLDAAWSL$ (SEQ ID NO: 1841)*DDPKLYDKDLGSAVWDTVVAQLDAAWSL (SEQ ID NO: 1842)*DDPKLYDKDLGSAVWDTVVAQLDAATSL$ (SEQ ID NO: 1843)*DDPKLYDKDLGSAVWDTVVAQLDAATSL (SEQ ID NO: 1844)*DDPKLYDKDLGSAVWDTVVAQLDAAWSL$ (SEQ ID NO: 1845)*DDPKLYDKDLGSAVWDTVVAQLDAAWSL (SEQ ID NO: 1846)*DDPKLYDKDLGSAVWDWVVAWVDAATSL$ (SEQ ID NO: 1847)*DDPKLYDKDLGSAVWDWVVAWVDAATSL (SEQ ID NO: 1848)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 1849)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 1850)*DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 1851)*DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 1852)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 1853)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 1854)*DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 1855)*DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 1856)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 1857)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 1858)*DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 1859)*DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 1860)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 1861)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 1862)*DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 1863)*DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 1864)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL$ (SEQ ID NO: 1865)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL (SEQ ID NO: 1866)*DDPKLYDKDLGSAVWDWVVAQMDAATSL$ (SEQ ID NO: 1867)*DDPKLYDKDLGSAVWDWVVAQMDAATSL (SEQ ID NO: 1868)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL$ (SEQ ID NO: 1869)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL (SEQ ID NO: 1870)*DDPKLYDKDLGSAVWDWVVGWVDAATSL$ (SEQ ID NO: 1871)*DDPKLYDKDLGSAVWDWVVGWVDAATSL (SEQ ID NO: 1872)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL$ (SEQ ID NO: 1873)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL (SEQ ID NO: 1874)*DDPKLYDKDLGSAVWDWVVGWLDAATSL$ (SEQ ID NO: 1875)*DDPKLYDKDLGSAVWDWVVGWLDAATSL (SEQ ID NO: 1876)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL$ (SEQ ID NO: 1877)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL (SEQ ID NO: 1878)*DDPKLYDKDLGSAVWDWVVGWMDAATSL$ (SEQ ID NO: 1879)*DDPKLYDKDLGSAVWDWVVGWMDAATSL (SEQ ID NO: 1880)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL$ (SEQ ID NO: 1881)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL (SEQ ID NO: 1882)*DDPKLYDKDLGSAVWDWVVGQVDAATSL$ (SEQ ID NO: 1883)*DDPKLYDKDLGSAVWDWVVGQVDAATSL (SEQ ID NO: 1884)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL$ (SEQ ID NO: 1885)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL (SEQ ID NO: 1886)*DDPKLYDKDLGSAVWDWVVGQLDAATSL$ (SEQ ID NO: 1887)*DDPKLYDKDLGSAVWDWVVGQLDAATSL (SEQ ID NO: 1888)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 1889)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 1890)*DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 1891)*DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 1892)*DDPKLYDKDLGSAVWDTVVAWVDAAWSL$ (SEQ ID NO: 1893)*DDPKLYDKDLGSAVWDTVVAWVDAAWSL (SEQ ID NO: 1894)*DDPKLYDKDLGSAVWDTVVAWVDAATSL$ (SEQ ID NO: 1895)*DDPKLYDKDLGSAVWDTVVAWVDAATSL (SEQ ID NO: 1896)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 1897)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 1898)*DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 1899)*DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 1900)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 1901)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 1902)*DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 1903)*DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 1904)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 1905)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 1906)*DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 1907)*DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 1908)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 1909)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 1910)*DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 1911)*DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 1912)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL$ (SEQ ID NO: 1913)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL (SEQ ID NO: 1914)*DDPKLYDKDLGSAVWDWVVAQMDAATSL$ (SEQ ID NO: 1915)*DDPKLYDKDLGSAVWDWVVAQMDAATSL (SEQ ID NO: 1916)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL$ (SEQ ID NO: 1917)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL (SEQ ID NO: 1918)*DDPKLYDKDLGSAVWDWVVGWVDAATSL$ (SEQ ID NO: 1919)*DDPKLYDKDLGSAVWDWVVGWVDAATSL (SEQ ID NO: 1920)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL$ (SEQ ID NO: 1921)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL (SEQ ID NO: 1922)*DDPKLYDKDLGSAVWDWVVGWLDAATSL$ (SEQ ID NO: 1923)*DDPKLYDKDLGSAVWDWVVGWLDAATSL (SEQ ID NO: 1924)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL$ (SEQ ID NO: 1925)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL (SEQ ID NO: 1926)*DDPKLYDKDLGSAVWDWVVGWMDAATSL$ (SEQ ID NO: 1927)*DDPKLYDKDLGSAVWDWVVGWMDAATSL (SEQ ID NO: 1928)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL$ (SEQ ID NO: 1929)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL (SEQ ID NO: 1930)*DDPKLYDKDLGSAVWDWVVGQVDAATSL$ (SEQ ID NO: 1931)*DDPKLYDKDLGSAVWDWVVGQVDAATSL (SEQ ID NO: 1932)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL$ (SEQ ID NO: 1933)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL (SEQ ID NO: 1934)*DDPKLYDKDLGSAVWDWVVGQLDAATSL$ (SEQ ID NO: 1935)*DDPKLYDKDLGSAVWDWVVGQLDAATSL (SEQ ID NO: 1936)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 1937)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 1938)*DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 1939)*DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 1940)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 1941)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 1942)*DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 1943)*DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 1944)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 1945)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 1946)*DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 1947)*DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 1948)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 1949)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 1950)*DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 1951)*DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 1952)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 1953)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 1954)*DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 1955)*DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 1956)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL$ (SEQ ID NO: 1957)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL (SEQ ID NO: 1958)*DDPKLYDKDLGSAVWDWVVAQMDAATSL$ (SEQ ID NO: 1959)*DDPKLYDKDLGSAVWDWVVAQMDAATSL (SEQ ID NO: 1960)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL$ (SEQ ID NO: 1961)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL (SEQ ID NO: 1962)*DDPKLYDKDLGSAVWDWVVGWVDAATSL$ (SEQ ID NO: 1963)*DDPKLYDKDLGSAVWDWVVGWVDAATSL (SEQ ID NO: 1964)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL$ (SEQ ID NO: 1965)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL (SEQ ID NO: 1966)*DDPKLYDKDLGSAVWDWVVGWLDAATSL$ (SEQ ID NO: 1967)*DDPKLYDKDLGSAVWDWVVGWLDAATSL (SEQ ID NO: 1968)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL$ (SEQ ID NO: 1969)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL (SEQ ID NO: 1970)*DDPKLYDKDLGSAVWDWVVGWMDAATSL$ (SEQ ID NO: 1971)*DDPKLYDKDLGSAVWDWVVGWMDAATSL (SEQ ID NO: 1972)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL$ (SEQ ID NO: 1973)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL (SEQ ID NO: 1974)*DDPKLYDKDLGSAVWDWVVGQVDAATSL$ (SEQ ID NO: 1975)*DDPKLYDKDLGSAVWDWVVGQVDAATSL (SEQ ID NO: 1976)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL$ (SEQ ID NO: 1977)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL (SEQ ID NO: 1978)*DDPKLYDKDLGSAVWDWVVGQLDAATSL$ (SEQ ID NO: 1979)*DDPKLYDKDLGSAVWDWVVGQLDAATSL (SEQ ID NO: 1980)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 1981)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 1982)*DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 1983)*DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 1984)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 1985)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 1986)*DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 1987)*DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 1988)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 1989)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 1990)*DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 1991)*DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 1992)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 1993)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 1994)*DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 1995)*DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 1996)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 1997)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 1998)*DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 1999)*DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2000)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL$ (SEQ ID NO: 2001)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL (SEQ ID NO: 2002)*DDPKLYDKDLGSAVWDWVVAQMDAATSL$ (SEQ ID NO: 2003)*DDPKLYDKDLGSAVWDWVVAQMDAATSL (SEQ ID NO: 2004)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL$ (SEQ ID NO: 2005)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL (SEQ ID NO: 2006)*DDPKLYDKDLGSAVWDWVVGWVDAATSL$ (SEQ ID NO: 2007)*DDPKLYDKDLGSAVWDWVVGWVDAATSL (SEQ ID NO: 2008)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL$ (SEQ ID NO: 2009)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL (SEQ ID NO: 2010)*DDPKLYDKDLGSAVWDWVVGWLDAATSL$ (SEQ ID NO: 2011)*DDPKLYDKDLGSAVWDWVVGWLDAATSL (SEQ ID NO: 2012)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL$ (SEQ ID NO: 2013)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL (SEQ ID NO: 2014)*DDPKLYDKDLGSAVWDWVVGWMDAATSL$ (SEQ ID NO: 2015)*DDPKLYDKDLGSAVWDWVVGWMDAATSL (SEQ ID NO: 2016)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL$ (SEQ ID NO: 2017)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL (SEQ ID NO: 2018)*DDPKLYDKDLGSAVWDWVVGQVDAATSL$ (SEQ ID NO: 2019)*DDPKLYDKDLGSAVWDWVVGQVDAATSL (SEQ ID NO: 2020)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL$ (SEQ ID NO: 2021)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL (SEQ ID NO: 2022)*DDPKLYDKDLGSAVWDWVVGQLDAATSL$ (SEQ ID NO: 2023)*DDPKLYDKDLGSAVWDWVVGQLDAATSL (SEQ ID NO: 2024)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2025)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2026)*DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2027)*DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2028)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2029)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2030)*DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2031)*DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2032)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2033)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2034)*DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2035)*DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2036)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2037)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2038)*DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2039)*DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2040)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2041)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2042)*DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2043)*DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2044)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL$ (SEQ ID NO: 2045)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL (SEQ ID NO: 2046)*DDPKLYDKDLGSAVWDWVVAQMDAATSL$ (SEQ ID NO: 2047)*DDPKLYDKDLGSAVWDWVVAQMDAATSL (SEQ ID NO: 2048)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL$ (SEQ ID NO: 2049)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL (SEQ ID NO: 2050)*DDPKLYDKDLGSAVWDWVVGWVDAATSL$ (SEQ ID NO: 2051)*DDPKLYDKDLGSAVWDWVVGWVDAATSL (SEQ ID NO: 2052)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL$ (SEQ ID NO: 2053)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL (SEQ ID NO: 2054)*DDPKLYDKDLGSAVWDWVVGWLDAATSL$ (SEQ ID NO: 2055)*DDPKLYDKDLGSAVWDWVVGWLDAATSL (SEQ ID NO: 2056)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL$ (SEQ ID NO: 2057)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL (SEQ ID NO: 2058)*DDPKLYDKDLGSAVWDWVVGWMDAATSL$ (SEQ ID NO: 2059)*DDPKLYDKDLGSAVWDWVVGWMDAATSL (SEQ ID NO: 2060)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL$ (SEQ ID NO: 2061)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL (SEQ ID NO: 2062)*DDPKLYDKDLGSAVWDWVVGQVDAATSL$ (SEQ ID NO: 2063)*DDPKLYDKDLGSAVWDWVVGQVDAATSL (SEQ ID NO: 2064)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL$ (SEQ ID NO: 2065)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL (SEQ ID NO: 2066)*DDPKLYDKDLGSAVWDWVVGQLDAATSL$ (SEQ ID NO: 2067)*DDPKLYDKDLGSAVWDWVVGQLDAATSL (SEQ ID NO: 2068)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2069)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2070)*DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2071)*DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2072)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2073)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2074)*DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2075)*DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2076)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2077)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2078)*DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2079)*DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2080)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2081)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2082)*DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2083)*DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2084)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2085)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2086)*DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2087)*DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2088)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL$ (SEQ ID NO: 2089)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL (SEQ ID NO: 2090)*DDPKLYDKDLGSAVWDWVVAQMDAATSL$ (SEQ ID NO: 2091)*DDPKLYDKDLGSAVWDWVVAQMDAATSL (SEQ ID NO: 2092)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL$ (SEQ ID NO: 2093)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL (SEQ ID NO: 2094)*DDPKLYDKDLGSAVWDWVVGWVDAATSL$ (SEQ ID NO: 2095)*DDPKLYDKDLGSAVWDWVVGWVDAATSL (SEQ ID NO: 2096)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL$ (SEQ ID NO: 2097)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL (SEQ ID NO: 2098)*DDPKLYDKDLGSAVWDWVVGWLDAATSL$ (SEQ ID NO: 2099)*DDPKLYDKDLGSAVWDWVVGWLDAATSL (SEQ ID NO: 2100)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL$ (SEQ ID NO: 2101)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL (SEQ ID NO: 2102)*DDPKLYDKDLGSAVWDWVVGWMDAATSL$ (SEQ ID NO: 2103)*DDPKLYDKDLGSAVWDWVVGWMDAATSL (SEQ ID NO: 2104)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL$ (SEQ ID NO: 2105)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL (SEQ ID NO: 2106)*DDPKLYDKDLGSAVWDWVVGQVDAATSL$ (SEQ ID NO: 2107)*DDPKLYDKDLGSAVWDWVVGQVDAATSL (SEQ ID NO: 2108)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL$ (SEQ ID NO: 2109)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL (SEQ ID NO: 2110)*DDPKLYDKDLGSAVWDWVVGQLDAATSL$ (SEQ ID NO: 2111)*DDPKLYDKDLGSAVWDWVVGQLDAATSL (SEQ ID NO: 2112)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2113)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2114)*DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2115)*DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2116)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2117)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2118)*DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2119)*DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2120)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2121)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2122)*DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2123)*DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2124)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2125)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2126)*DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2127)*DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2128)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2129)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2130)*DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2131)*DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2132)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL$ (SEQ ID NO: 2133)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL (SEQ ID NO: 2134)*DDPKLYDKDLGSAVWDWVVAQMDAATSL$ (SEQ ID NO: 2135)*DDPKLYDKDLGSAVWDWVVAQMDAATSL (SEQ ID NO: 2136)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL$ (SEQ ID NO: 2137)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL (SEQ ID NO: 2138)*DDPKLYDKDLGSAVWDWVVGWVDAATSL$ (SEQ ID NO: 2139)*DDPKLYDKDLGSAVWDWVVGWVDAATSL (SEQ ID NO: 2140)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL$ (SEQ ID NO: 2141)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL (SEQ ID NO: 2142)*DDPKLYDKDLGSAVWDWVVGWLDAATSL$ (SEQ ID NO: 2143)*DDPKLYDKDLGSAVWDWVVGWLDAATSL (SEQ ID NO: 2144)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL$ (SEQ ID NO: 2145)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL (SEQ ID NO: 2146)*DDPKLYDKDLGSAVWDWVVGWMDAATSL$ (SEQ ID NO: 2147)*DDPKLYDKDLGSAVWDWVVGWMDAATSL (SEQ ID NO: 2148)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL$ (SEQ ID NO: 2149)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL (SEQ ID NO: 2150)*DDPKLYDKDLGSAVWDWVVGQVDAATSL$ (SEQ ID NO: 2151)*DDPKLYDKDLGSAVWDWVVGQVDAATSL (SEQ ID NO: 2152)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL$ (SEQ ID NO: 2153)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL (SEQ ID NO: 2154)*DDPKLYDKDLGSAVWDWVVGQLDAATSL$ (SEQ ID NO: 2155)*DDPKLYDKDLGSAVWDWVVGQLDAATSL (SEQ ID NO: 2156)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2157)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2158)*DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2159)*DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2160)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2161)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2162)*DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2163)*DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2164)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2165)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2166)*DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2167)*DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2168)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2169)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2170)*DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2171)*DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2172)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2173)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2174)*DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2175)*DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2176)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL$ (SEQ ID NO: 2177)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL (SEQ ID NO: 2178)*DDPKLYDKDLGSAVWDWVVAQMDAATSL$ (SEQ ID NO: 2179)*DDPKLYDKDLGSAVWDWVVAQMDAATSL (SEQ ID NO: 2180)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL$ (SEQ ID NO: 2181)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL (SEQ ID NO: 2182)*DDPKLYDKDLGSAVWDWVVGWVDAATSL$ (SEQ ID NO: 2183)*DDPKLYDKDLGSAVWDWVVGWVDAATSL (SEQ ID NO: 2184)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL$ (SEQ ID NO: 2185)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL (SEQ ID NO: 2186)*DDPKLYDKDLGSAVWDWVVGWLDAATSL$ (SEQ ID NO: 2187)*DDPKLYDKDLGSAVWDWVVGWLDAATSL (SEQ ID NO: 2188)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL$ (SEQ ID NO: 2189)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL (SEQ ID NO: 2190)*DDPKLYDKDLGSAVWDWVVGWMDAATSL$ (SEQ ID NO: 2191)*DDPKLYDKDLGSAVWDWVVGWMDAATSL (SEQ ID NO: 2192)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL$ (SEQ ID NO: 2193)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL (SEQ ID NO: 2194)*DDPKLYDKDLGSAVWDWVVGQVDAATSL$ (SEQ ID NO: 2195)*DDPKLYDKDLGSAVWDWVVGQVDAATSL (SEQ ID NO: 2196)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL$ (SEQ ID NO: 2197)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL (SEQ ID NO: 2198)*DDPKLYDKDLGSAVWDWVVGQLDAATSL$ (SEQ ID NO: 2199)*DDPKLYDKDLGSAVWDWVVGQLDAATSL (SEQ ID NO: 2200)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2201)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2202)*DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2203)*DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2204)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2205)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2206)*DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2207)*DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2208)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2209)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2210)*DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2211)*DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2212)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2213)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2214)*DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2215)*DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2216)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2217)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2218)*DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2219)*DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2220)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL$ (SEQ ID NO: 2221)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL (SEQ ID NO: 2222)*DDPKLYDKDLGSAVWDWVVAQMDAATSL$ (SEQ ID NO: 2223)*DDPKLYDKDLGSAVWDWVVAQMDAATSL (SEQ ID NO: 2224)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL$ (SEQ ID NO: 2225)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL (SEQ ID NO: 2226)*DDPKLYDKDLGSAVWDWVVGWVDAATSL$ (SEQ ID NO: 2227)*DDPKLYDKDLGSAVWDWVVGWVDAATSL (SEQ ID NO: 2228)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL$ (SEQ ID NO: 2229)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL (SEQ ID NO: 2230)*DDPKLYDKDLGSAVWDWVVGWLDAATSL$ (SEQ ID NO: 2231)*DDPKLYDKDLGSAVWDWVVGWLDAATSL (SEQ ID NO: 2232)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL$ (SEQ ID NO: 2233)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL (SEQ ID NO: 2234)*DDPKLYDKDLGSAVWDWVVGWMDAATSL$ (SEQ ID NO: 2235)*DDPKLYDKDLGSAVWDWVVGWMDAATSL (SEQ ID NO: 2236)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL$ (SEQ ID NO: 2237)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL (SEQ ID NO: 2238)*DDPKLYDKDLGSAVWDWVVGQVDAATSL$ (SEQ ID NO: 2239)*DDPKLYDKDLGSAVWDWVVGQVDAATSL (SEQ ID NO: 2240)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL$ (SEQ ID NO: 2241)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL (SEQ ID NO: 2242)*DDPKLYDKDLGSAVWDWVVGQLDAATSL$ (SEQ ID NO: 2243)*DDPKLYDKDLGSAVWDWVVGQLDAATSL (SEQ ID NO: 2244)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2245)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2246)*DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2247)*DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2248)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2249)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2250)*DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2251)*DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2252)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2253)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2254)*DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2255)*DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2256)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2257)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2258)*DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2259)*DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2260)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2261)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2262)*DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2263)*DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2264)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL$ (SEQ ID NO: 2265)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL (SEQ ID NO: 2266)*DDPKLYDKDLGSAVWDWVVAQMDAATSL$ (SEQ ID NO: 2267)*DDPKLYDKDLGSAVWDWVVAQMDAATSL (SEQ ID NO: 2268)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL$ (SEQ ID NO: 2269)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL (SEQ ID NO: 2270)*DDPKLYDKDLGSAVWDWVVGWVDAATSL$ (SEQ ID NO: 2271)*DDPKLYDKDLGSAVWDWVVGWVDAATSL (SEQ ID NO: 2272)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL$ (SEQ ID NO: 2273)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL (SEQ ID NO: 2274)*DDPKLYDKDLGSAVWDWVVGWLDAATSL$ (SEQ ID NO: 2275)*DDPKLYDKDLGSAVWDWVVGWLDAATSL (SEQ ID NO: 2276)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL$ (SEQ ID NO: 2277)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL (SEQ ID NO: 2278)*DDPKLYDKDLGSAVWDWVVGWMDAATSL$ (SEQ ID NO: 2279)*DDPKLYDKDLGSAVWDWVVGWMDAATSL (SEQ ID NO: 2280)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL$ (SEQ ID NO: 2281)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL (SEQ ID NO: 2282)*DDPKLYDKDLGSAVWDWVVGQVDAATSL$ (SEQ ID NO: 2283)*DDPKLYDKDLGSAVWDWVVGQVDAATSL (SEQ ID NO: 2284)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL$ (SEQ ID NO: 2285)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL (SEQ ID NO: 2286)*DDPKLYDKDLGSAVWDWVVGQLDAATSL$ (SEQ ID NO: 2287)*DDPKLYDKDLGSAVWDWVVGQLDAATSL (SEQ ID NO: 2288)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2289)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2290)*DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2291)*DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2292)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2293)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2294)*DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2295)*DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2296)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2297)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2298)*DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2299)*DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2300)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2301)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2302)*DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2303)*DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2304)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2305)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2306)*DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2307)*DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2308)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL$ (SEQ ID NO: 2309)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL (SEQ ID NO: 2310)*DDPKLYDKDLGSAVWDWVVAQMDAATSL$ (SEQ ID NO: 2311)*DDPKLYDKDLGSAVWDWVVAQMDAATSL (SEQ ID NO: 2312)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL$ (SEQ ID NO: 2313)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL (SEQ ID NO: 2314)*DDPKLYDKDLGSAVWDWVVGWVDAATSL$ (SEQ ID NO: 2315)*DDPKLYDKDLGSAVWDWVVGWVDAATSL (SEQ ID NO: 2316)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL$ (SEQ ID NO: 2317)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL (SEQ ID NO: 2318)*DDPKLYDKDLGSAVWDWVVGWLDAATSL$ (SEQ ID NO: 2319)*DDPKLYDKDLGSAVWDWVVGWLDAATSL (SEQ ID NO: 2320)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL$ (SEQ ID NO: 2321)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL (SEQ ID NO: 2322)*DDPKLYDKDLGSAVWDWVVGWMDAATSL$ (SEQ ID NO: 2323)*DDPKLYDKDLGSAVWDWVVGWMDAATSL (SEQ ID NO: 2324)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL$ (SEQ ID NO: 2325)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL (SEQ ID NO: 2326)*DDPKLYDKDLGSAVWDWVVGQVDAATSL$ (SEQ ID NO: 2327)*DDPKLYDKDLGSAVWDWVVGQVDAATSL (SEQ ID NO: 2328)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL$ (SEQ ID NO: 2329)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL (SEQ ID NO: 2330)*DDPKLYDKDLGSAVWDWVVGQLDAATSL$ (SEQ ID NO: 2331)*DDPKLYDKDLGSAVWDWVVGQLDAATSL (SEQ ID NO: 2332)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2333)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2334)*DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2335)*DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2336)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2337)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2338)*DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2339)*DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2340)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2341)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2342)*DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2343)*DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2344)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2345)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2346)*DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2347)*DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2348)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2349)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2350)*DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2351)*DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2352)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL$ (SEQ ID NO: 2353)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL (SEQ ID NO: 2354)*DDPKLYDKDLGSAVWDWVVAQMDAATSL$ (SEQ ID NO: 2355)*DDPKLYDKDLGSAVWDWVVAQMDAATSL (SEQ ID NO: 2356)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL$ (SEQ ID NO: 2357)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL (SEQ ID NO: 2358)*DDPKLYDKDLGSAVWDWVVGWVDAATSL$ (SEQ ID NO: 2359)*DDPKLYDKDLGSAVWDWVVGWVDAATSL (SEQ ID NO: 2360)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL$ (SEQ ID NO: 2361)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL (SEQ ID NO: 2362)*DDPKLYDKDLGSAVWDWVVGWLDAATSL$ (SEQ ID NO: 2363)*DDPKLYDKDLGSAVWDWVVGWLDAATSL (SEQ ID NO: 2364)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL$ (SEQ ID NO: 2365)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL (SEQ ID NO: 2366)*DDPKLYDKDLGSAVWDWVVGWMDAATSL$ (SEQ ID NO: 2367)*DDPKLYDKDLGSAVWDWVVGWMDAATSL (SEQ ID NO: 2368)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL$ (SEQ ID NO: 2369)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL (SEQ ID NO: 2370)*DDPKLYDKDLGSAVWDWVVGQVDAATSL$ (SEQ ID NO: 2371)*DDPKLYDKDLGSAVWDWVVGQVDAATSL (SEQ ID NO: 2372)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL$ (SEQ ID NO: 2373)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL (SEQ ID NO: 2374)*DDPKLYDKDLGSAVWDWVVGQLDAATSL$ (SEQ ID NO: 2375)*DDPKLYDKDLGSAVWDWVVGQLDAATSL (SEQ ID NO: 2376)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2377)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2378)*DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2379)*DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2380)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2381)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2382)*DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2383)*DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2384)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2385)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2386)*DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2387)*DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2388)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2389)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2390)*DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2391)*DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2392)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2393)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2394)*DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2395)*DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2396)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL$ (SEQ ID NO: 2397)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL (SEQ ID NO: 2398)*DDPKLYDKDLGSAVWDWVVAQMDAATSL$ (SEQ ID NO: 2399)*DDPKLYDKDLGSAVWDWVVAQMDAATSL (SEQ ID NO: 2400)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL$ (SEQ ID NO: 2401)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL (SEQ ID NO: 2402)*DDPKLYDKDLGSAVWDWVVGWVDAATSL$ (SEQ ID NO: 2403)*DDPKLYDKDLGSAVWDWVVGWVDAATSL (SEQ ID NO: 2404)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL$ (SEQ ID NO: 2405)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL (SEQ ID NO: 2406)*DDPKLYDKDLGSAVWDWVVGWLDAATSL$ (SEQ ID NO: 2407)*DDPKLYDKDLGSAVWDWVVGWLDAATSL (SEQ ID NO: 2408)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL$ (SEQ ID NO: 2409)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL (SEQ ID NO: 2410)*DDPKLYDKDLGSAVWDWVVGWMDAATSL$ (SEQ ID NO: 2411)*DDPKLYDKDLGSAVWDWVVGWMDAATSL (SEQ ID NO: 2412)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL$ (SEQ ID NO: 2413)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL (SEQ ID NO: 2414)*DDPKLYDKDLGSAVWDWVVGQVDAATSL$ (SEQ ID NO: 2415)*DDPKLYDKDLGSAVWDWVVGQVDAATSL (SEQ ID NO: 2416)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL$ (SEQ ID NO: 2417)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL (SEQ ID NO: 2418)*DDPKLYDKDLGSAVWDWVVGQLDAATSL$ (SEQ ID NO: 2419)*DDPKLYDKDLGSAVWDWVVGQLDAATSL (SEQ ID NO: 2420)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2421)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2422)*DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2423)*DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2424)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2425)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2426)*DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2427)*DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2428)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2429)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2430)*DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2431)*DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2432)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2433)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2434)*DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2435)*DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2436)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2437)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2438)*DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2439)*DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2440)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL$ (SEQ ID NO: 2441)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL (SEQ ID NO: 2442)*DDPKLYDKDLGSAVWDWVVAQMDAATSL$ (SEQ ID NO: 2443)*DDPKLYDKDLGSAVWDWVVAQMDAATSL (SEQ ID NO: 2444)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL$ (SEQ ID NO: 2445)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL (SEQ ID NO: 2446)*DDPKLYDKDLGSAVWDWVVGWVDAATSL$ (SEQ ID NO: 2447)*DDPKLYDKDLGSAVWDWVVGWVDAATSL (SEQ ID NO: 2448)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL$ (SEQ ID NO: 2449)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL (SEQ ID NO: 2450)*DDPKLYDKDLGSAVWDWVVGWLDAATSL$ (SEQ ID NO: 2451)*DDPKLYDKDLGSAVWDWVVGWLDAATSL (SEQ ID NO: 2452)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL$ (SEQ ID NO: 2453)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL (SEQ ID NO: 2454)*DDPKLYDKDLGSAVWDWVVGWMDAATSL$ (SEQ ID NO: 2455)*DDPKLYDKDLGSAVWDWVVGWMDAATSL (SEQ ID NO: 2456)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL$ (SEQ ID NO: 2457)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL (SEQ ID NO: 2458)*DDPKLYDKDLGSAVWDWVVGQVDAATSL$ (SEQ ID NO: 2459)*DDPKLYDKDLGSAVWDWVVGQVDAATSL (SEQ ID NO: 2460)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL$ (SEQ ID NO: 2461)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL (SEQ ID NO: 2462)*DDPKLYDKDLGSAVWDWVVGQLDAATSL$ (SEQ ID NO: 2463)*DDPKLYDKDLGSAVWDWVVGQLDAATSL (SEQ ID NO: 2464)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2465)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2466)*DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2467)*DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2468)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2469)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2470)*DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2471)*DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2472)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2473)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2474)*DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2475)*DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2476)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2477)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2478)*DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2479)*DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2480)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2481)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2482)*DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2483)*DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2484)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL$ (SEQ ID NO: 2485)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL (SEQ ID NO: 2486)*DDPKLYDKDLGSAVWDWVVAQMDAATSL$ (SEQ ID NO: 2487)*DDPKLYDKDLGSAVWDWVVAQMDAATSL (SEQ ID NO: 2488)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL$ (SEQ ID NO: 2489)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL (SEQ ID NO: 2490)*DDPKLYDKDLGSAVWDWVVGWVDAATSL$ (SEQ ID NO: 2491)*DDPKLYDKDLGSAVWDWVVGWVDAATSL (SEQ ID NO: 2492)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL$ (SEQ ID NO: 2493)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL (SEQ ID NO: 2494)*DDPKLYDKDLGSAVWDWVVGWLDAATSL$ (SEQ ID NO: 2495)*DDPKLYDKDLGSAVWDWVVGWLDAATSL (SEQ ID NO: 2496)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL$ (SEQ ID NO: 2497)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL (SEQ ID NO: 2498)*DDPKLYDKDLGSAVWDWVVGWMDAATSL$ (SEQ ID NO: 2499)*DDPKLYDKDLGSAVWDWVVGWMDAATSL (SEQ ID NO: 2500)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL$ (SEQ ID NO: 2501)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL (SEQ ID NO: 2502)*DDPKLYDKDLGSAVWDWVVGQVDAATSL$ (SEQ ID NO: 2503)*DDPKLYDKDLGSAVWDWVVGQVDAATSL (SEQ ID NO: 2504)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL$ (SEQ ID NO: 2505)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL (SEQ ID NO: 2506)*DDPKLYDKDLGSAVWDWVVGQLDAATSL$ (SEQ ID NO: 2507)*DDPKLYDKDLGSAVWDWVVGQLDAATSL (SEQ ID NO: 2508)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2509)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2510)*DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2511)*DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2512)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2513)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2514)*DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2515)*DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2516)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2517)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2518)*DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2519)*DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2520)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2521)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2522)*DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2523)*DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2524)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2525)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2526)*DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2527)*DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2528)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL$ (SEQ ID NO: 2529)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL (SEQ ID NO: 2530)*DDPKLYDKDLGSAVWDWVVAQMDAATSL$ (SEQ ID NO: 2531)*DDPKLYDKDLGSAVWDWVVAQMDAATSL (SEQ ID NO: 2532)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL$ (SEQ ID NO: 2533)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL (SEQ ID NO: 2534)*DDPKLYDKDLGSAVWDWVVGWVDAATSL$ (SEQ ID NO: 2535)*DDPKLYDKDLGSAVWDWVVGWVDAATSL (SEQ ID NO: 2536)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL$ (SEQ ID NO: 2537)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL (SEQ ID NO: 2538)*DDPKLYDKDLGSAVWDWVVGWLDAATSL$ (SEQ ID NO: 2539)*DDPKLYDKDLGSAVWDWVVGWLDAATSL (SEQ ID NO: 2540)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL$ (SEQ ID NO: 2541)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL (SEQ ID NO: 2542)*DDPKLYDKDLGSAVWDWVVGWMDAATSL$ (SEQ ID NO: 2543)*DDPKLYDKDLGSAVWDWVVGWMDAATSL (SEQ ID NO: 2544)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL$ (SEQ ID NO: 2545)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL (SEQ ID NO: 2546)*DDPKLYDKDLGSAVWDWVVGQVDAATSL$ (SEQ ID NO: 2547)*DDPKLYDKDLGSAVWDWVVGQVDAATSL (SEQ ID NO: 2548)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL$ (SEQ ID NO: 2549)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL (SEQ ID NO: 2550)*DDPKLYDKDLGSAVWDWVVGQLDAATSL$ (SEQ ID NO: 2551)*DDPKLYDKDLGSAVWDWVVGQLDAATSL (SEQ ID NO: 2552)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2553)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2554)*DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2555)*DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2556)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2557)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2558)*DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2559)*DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2560)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2561)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2562)*DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2563)*DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2564)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2565)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2566)*DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2567)*DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2568)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2569)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2570)*DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2571)*DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2572)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL$ (SEQ ID NO: 2573)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL (SEQ ID NO: 2574)*DDPKLYDKDLGSAVWDWVVAQMDAATSL$ (SEQ ID NO: 2575)*DDPKLYDKDLGSAVWDWVVAQMDAATSL (SEQ ID NO: 2576)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL$ (SEQ ID NO: 2577)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL (SEQ ID NO: 2578)*DDPKLYDKDLGSAVWDWVVGWVDAATSL$ (SEQ ID NO: 2579)*DDPKLYDKDLGSAVWDWVVGWVDAATSL (SEQ ID NO: 2580)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL$ (SEQ ID NO: 2581)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL (SEQ ID NO: 2582)*DDPKLYDKDLGSAVWDWVVGWLDAATSL$ (SEQ ID NO: 2583)*DDPKLYDKDLGSAVWDWVVGWLDAATSL (SEQ ID NO: 2584)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL$ (SEQ ID NO: 2585)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL (SEQ ID NO: 2586)*DDPKLYDKDLGSAVWDWVVGWMDAATSL$ (SEQ ID NO: 2587)*DDPKLYDKDLGSAVWDWVVGWMDAATSL (SEQ ID NO: 2588)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL$ (SEQ ID NO: 2589)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL (SEQ ID NO: 2590)*DDPKLYDKDLGSAVWDWVVGQVDAATSL$ (SEQ ID NO: 2591)*DDPKLYDKDLGSAVWDWVVGQVDAATSL (SEQ ID NO: 2592)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL$ (SEQ ID NO: 2593)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL (SEQ ID NO: 2594)*DDPKLYDKDLGSAVWDWVVGQLDAATSL$ (SEQ ID NO: 2595)*DDPKLYDKDLGSAVWDWVVGQLDAATSL (SEQ ID NO: 2596)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2597)*DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2598)*DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2599)*DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2600)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2601)*DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2602)*DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2603)*DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2604)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2605)*DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2606)*DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2607)*DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2608)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2609)*DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2610)*DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2611)*DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2612)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2613)*DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2614)*DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2615)*DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2616)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL$ (SEQ ID NO: 2617)*DDPKLYDKDLGSAVWDWVVAQMDAAWSL (SEQ ID NO: 2618)*DDPKLYDKDLGSAVWDWVVAQMDAATSL$ (SEQ ID NO: 2619)*DDPKLYDKDLGSAVWDWVVAQMDAATSL (SEQ ID NO: 2620)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL$ (SEQ ID NO: 2621)*DDPKLYDKDLGSAVWDWVVGWVDAAWSL (SEQ ID NO: 2622)*DDPKLYDKDLGSAVWDWVVGWVDAATSL$ (SEQ ID NO: 2623)*DDPKLYDKDLGSAVWDWVVGWVDAATSL (SEQ ID NO: 2624)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL$ (SEQ ID NO: 2625)*DDPKLYDKDLGSAVWDWVVGWLDAAWSL (SEQ ID NO: 2626)*DDPKLYDKDLGSAVWDWVVGWLDAATSL$ (SEQ ID NO: 2627)*DDPKLYDKDLGSAVWDWVVGWLDAATSL (SEQ ID NO: 2628)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL$ (SEQ ID NO: 2629)*DDPKLYDKDLGSAVWDWVVGWMDAAWSL (SEQ ID NO: 2630)*DDPKLYDKDLGSAVWDWVVGWMDAATSL$ (SEQ ID NO: 2631)*DDPKLYDKDLGSAVWDWVVGWMDAATSL (SEQ ID NO: 2632)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL$ (SEQ ID NO: 2633)*DDPKLYDKDLGSAVWDWVVGQVDAAWSL (SEQ ID NO: 2634)*DDPKLYDKDLGSAVWDWVVGQVDAATSL$ (SEQ ID NO: 2635)*DDPKLYDKDLGSAVWDWVVGQVDAATSL (SEQ ID NO: 2636)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL$ (SEQ ID NO: 2637)*DDPKLYDKDLGSAVWDWVVGQLDAAWSL (SEQ ID NO: 2638)*DDPKLYDKDLGSAVWDWVVGQLDAATSL$ (SEQ ID NO: 2639)*DDPKLYDKDLGSAVWDWVVGQLDAATSL (SEQ ID NO: 2640)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2641)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2642)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2643)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2644)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2645)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2646)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2647)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2648)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2649)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2650)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2651)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2652)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2653)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2654)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2655)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2656)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2657)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2658)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2659)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2660)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2661)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2662)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2663)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2664)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2665)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2666)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2667)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2668)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2669)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2670)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2671)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2672)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2673)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2674)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2675)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2676)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2677)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2678)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2679)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2680)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2681)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2682)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2683)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2684)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2685)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2686)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2687)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2688)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2689)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2690)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2691)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2692)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2693)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2694)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2695)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2696)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2697)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2698)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2699)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2700)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2701)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2702)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2703)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2704)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2705)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2706)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2707)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2708)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2709)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2710)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2711)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2712)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2713)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2714)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2715)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2716)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2717)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2718)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2719)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2720)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2721)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2722)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2723)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2724)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2725)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2726)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2727)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2728)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2729)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2730)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2731)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2732)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2733)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2734)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2735)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2736)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2737)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2738)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2739)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2740)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2741)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2742)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2743)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2744)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2745)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2746)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2747)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2748)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2749)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2750)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2751)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2752)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2753)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2754)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2755)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2756)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2757)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2758)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2759)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2760)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2761)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2762)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2763)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2764)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2765)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2766)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2767)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2768)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2769)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2770)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2771)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2772)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2773)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2774)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2775)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2776)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2777)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2778)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2779)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2780)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2781)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2782)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2783)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2784)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2785)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2786)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2787)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2788)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2789)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2790)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2791)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2792)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2793)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2794)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2795)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2796)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2797)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2798)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2799)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2700)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2701)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2702)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2703)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2704)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2705)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2706)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2707)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2708)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2709)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2710)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2711)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2712)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2713)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2714)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2715)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2716)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2717)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2718)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2719)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2720)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2721)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2722)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2723)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2724)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2725)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2726)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2727)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2728)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2729)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2730)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2731)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2732)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2733)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2734)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2735)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2736)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2737)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2738)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2739)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2740)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2741)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2742)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2743)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2744)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2745)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2746)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2747)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2748)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2749)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2750)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2751)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2752)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2753)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2754)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2755)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2756)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2757)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2758)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2759)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2760)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2761)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2762)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2763)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2764)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2765)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2766)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2767)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2768)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2769)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2770)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2771)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2772)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2773)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2774)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2775)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2776)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2777)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2778)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2779)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2780)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2781)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2782)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2783)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2784)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2785)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2786)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2787)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2788)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2789)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2790)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2791)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2792)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2793)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2794)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2795)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2796)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2797)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2798)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2799)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2800)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2801)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2802)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2803)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2804)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2805)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2806)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2807)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2808)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2809)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2810)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2811)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2812)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2813)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2814)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2815)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2816)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2817)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2818)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2819)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2820)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2821)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2822)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2823)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2824)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2825)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2826)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2827)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2828)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2829)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2830)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2831)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2832)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2833)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2834)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2835)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2836)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2837)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2838)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2839)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2840)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2841)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2842)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2843)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2844)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2845)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2846)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2847)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2848)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2849)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2850)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2851)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2852)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2853)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2854)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2855)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2856)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2857)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2858)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2859)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2860)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2861)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2862)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2863)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2864)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2865)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2866)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2867)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2868)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2869)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2870)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2871)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2872)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2873)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2874)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2875)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2876)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2877)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2878)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2879)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2880)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2881)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2882)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2883)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2884)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2885)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2886)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2887)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2888)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2889)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2890)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2891)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2892)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2893)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2894)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2895)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2896)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2897)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2898)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2899)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2900)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2901)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2902)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2903)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2904)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2905)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2906)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2907)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2908)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2909)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2910)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2911)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2912)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2913)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2914)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2915)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2916)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2917)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2918)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2919)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2920)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2921)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2922)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2923)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2924)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2925)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2926)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2927)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2928)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2929)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2930)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2931)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2932)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2933)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2934)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2935)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2936)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2937)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2938)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2939)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2940)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2941)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2942)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2943)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2944)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2945)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2946)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2947)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2948)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2949)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2950)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2951)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2952)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2953)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2954)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2955)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2956)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2957)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2958)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2959)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2960)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2961)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2962)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2963)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2964)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2965)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2966)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2967)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2968)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2969)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2970)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2971)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2972)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2973)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2974)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2975)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2976)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2977)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2978)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2979)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 2980)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 2981)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 2982)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 2983)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 2984)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 2985)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 2986)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 2987)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 2988)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 2989)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 2990)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 2991)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 2992)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 2993)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 2994)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 2995)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 2996)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 2997)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 2998)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 2999)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 3000)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 3001)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 3002)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 3003)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 3004)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 3005)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 3006)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 3007)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 3008)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 3009)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 3010)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 3011)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 3012)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 3013)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 3014)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 3015)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 3016)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 3017)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 3018)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 3019)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 3020)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 3021)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 3022)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 3023)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 3024)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 3025)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 3026)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 3027)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 3028)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 3029)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 3030)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 3031)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 3032)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 3033)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 3034)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 3035)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 3036)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 3037)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 3038)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 3039)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 3040)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 3041)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 3042)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 3043)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 3044)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 3045)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 3046)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 3047)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 3048)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 3049)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 3050)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 3051)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 3052)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 3053)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 3054)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 3055)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 3056)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 3057)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 3058)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 3059)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 3060)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 3061)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 3062)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 3063)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 3064)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 3065)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 3066)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 3067)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 3068)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 3069)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 3070)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 3071)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 3072)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 3073)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 3074)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 3075)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 3076)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 3077)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 3078)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 3079)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 3080)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 3081)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 3082)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 3083)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 3084)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 3085)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 3086)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 3087)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 3088)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 3089)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 3090)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 3091)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 3092)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 3093)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 3094)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 3095)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 3096)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 3097)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 3098)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 3099)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 3100)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 3101)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 3102)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 3103)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 3104)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 3105)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 3106)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 3107)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 3108)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 3109)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 3110)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 3111)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 3112)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 3113)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 3114)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 3115)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 3116)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 3117)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 3118)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 3119)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 3120)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 3121)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 3122)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 3123)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 3124)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 3125)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 3126)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 3127)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 3128)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 3129)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 3130)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 3131)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 3132)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 3133)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 3134)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 3135)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 3136)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 3137)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 3138)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 3139)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 3140)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 3141)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 3142)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 3143)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 3144)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 3145)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 3146)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 3147)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 3148)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 3149)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 3150)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 3151)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 3152)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 3153)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 3154)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 3155)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 3156)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 3157)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 3158)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 3159)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 3160)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 3161)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 3162)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 3163)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 3164)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 3165)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 3166)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 3167)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 3168)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 3169)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 3170)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 3171)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 3172)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 3173)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 3174)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 3175)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 3176)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 3177)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 3178)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 3179)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 3180)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 3181)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 3182)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 3183)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 3184)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 3185)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 3186)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 3187)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 3188)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 3189)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 3190)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 3191)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 3192)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 3193)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 3194)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 3195)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 3196)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 3197)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 3198)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 3199)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 3200)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 3201)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 3202)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 3203)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 3204)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 3205)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 3206)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 3207)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 3208)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 3209)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 3210)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 3211)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 3212)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 3213)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 3214)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 3215)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 3216)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 3217)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 3218)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 3219)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 3220)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 3221)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 3222)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 3223)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 3224)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 3225)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 3226)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 3227)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 3228)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 3229)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 3230)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 3231)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 3232)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 3233)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 3234)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 3235)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 3236)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 3237)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 3238)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 3239)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 3240)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 3241)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 3242)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 3243)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 3244)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 3245)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 3246)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 3247)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 3248)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 3249)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 3250)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 3251)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 3252)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 3253)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 3254)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 3255)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 3256)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 3257)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 3258)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 3259)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 3260)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 3261)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 3262)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 3263)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 3264)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 3265)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 3266)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 3267)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 3268)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 3269)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 3270)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 3271)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 3272)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 3273)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 3274)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 3275)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 3276)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 3277)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 3278)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 3279)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 3280)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 3281)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 3282)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 3283)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 3284)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 3285)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 3286)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 3287)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 3288)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 3289)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 3290)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 3291)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 3292)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 3293)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 3294)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 3295)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 3296)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 3297)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 3298)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 3299)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 3300)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 3301)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 3302)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 3303)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 3304)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 3305)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 3306)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 3307)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 3308)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 3309)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 3310)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 3311)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 3312)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 3313)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 3314)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 3315)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 3316)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 3317)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 3318)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 3319)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 3320)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 3321)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 3322)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 3323)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 3324)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 3325)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 3326)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 3327)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 3328)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 3329)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 3330)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 3331)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 3332)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 3333)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 3334)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 3335)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 3336)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 3337)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 3338)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 3339)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 3340)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 3341)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 3342)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 3343)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 3344)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 3345)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 3346)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 3347)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 3348)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 3349)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 3350)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 3351)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 3352)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 3353)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 3354)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 3355)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 3356)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 3357)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 3358)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 3359)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 3360)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 3361)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 3362)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 3363)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 3364)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 3365)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 3366)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 3367)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 3368)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 3369)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 3370)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 3371)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 3372)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 3373)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 3374)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 3375)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 3376)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 3377)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 3378)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 3379)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 3380)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 3381)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 3382)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 3383)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 3384)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 3385)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 3386)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 3387)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 3388)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 3389)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 3390)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 3391)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 3392)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 3393)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 3394)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 3395)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 3396)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 3397)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 3398)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 3399)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 3400)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 3401)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 3402)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 3403)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 3404)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 3405)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 3406)DDPKLYDKDLGSAVWDWVVAQVDAATSL$ (SEQ ID NO: 3407)DDPKLYDKDLGSAVWDWVVAQVDAATSL (SEQ ID NO: 3408)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 3409)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 3410)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 3411)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 3412)DDPKLYDKDLGSAVWDWVVAQLDAAWSL$ (SEQ ID NO: 3413)DDPKLYDKDLGSAVWDWVVAQLDAAWSL (SEQ ID NO: 3414)DDPKLYDKDLGSAVWDWVVAQLDAATSL$ (SEQ ID NO: 3415)DDPKLYDKDLGSAVWDWVVAQLDAATSL (SEQ ID NO: 3416)DDPKLYDKDLGSAVWDWVVGQMDAAWSL$ (SEQ ID NO: 3417)DDPKLYDKDLGSAVWDWVVGQMDAAWSL (SEQ ID NO: 3418)DDPKLYDKDLGSAVWDWVVGQMDAATSL$ (SEQ ID NO: 3419)DDPKLYDKDLGSAVWDWVVGQMDAATSL (SEQ ID NO: 3420)DDPKLYDKDLGSAVWDWVVAWLDAAWSL$ (SEQ ID NO: 3421)DDPKLYDKDLGSAVWDWVVAWLDAAWSL (SEQ ID NO: 3422)DDPKLYDKDLGSAVWDWVVAWLDAATSL$ (SEQ ID NO: 3423)DDPKLYDKDLGSAVWDWVVAWLDAATSL (SEQ ID NO: 3424)DDPKLYDKDLGSAVWDWVVAWMDAAWSL$ (SEQ ID NO: 3425)DDPKLYDKDLGSAVWDWVVAWMDAAWSL (SEQ ID NO: 3426)DDPKLYDKDLGSAVWDWVVAWMDAATSL$ (SEQ ID NO: 3427)DDPKLYDKDLGSAVWDWVVAWMDAATSL (SEQ ID NO: 3428)DDPKLYDKDLGSAVWDWVVAQVDAAWSL$ (SEQ ID NO: 3429)DDPKLYDKDLGSAVWDWVVAQVDAAWSL (SEQ ID NO: 3430)DDPKLYDKDLGSAMGDWVVGWMDAATSL$ (SEQ ID NO: 3431)DDPKLYDKDLGSAMGDWVVGWMDAATSL (SEQ ID NO: 3432)DDPKLYDKDLGSAMGDWVVGQVDAAWSL$ (SEQ ID NO: 3433)DDPKLYDKDLGSAMGDWVVGQVDAAWSL (SEQ ID NO: 3434)DDPKLYDKDLGSAMGDWVVGWMDAATSL$ (SEQ ID NO: 3435)DDPKLYDKDLGSAMGDWVVGWMDAATSL (SEQ ID NO: 3436)DDPKLYDKDLGSAMGDWVVGWLDAAWSL$ (SEQ ID NO: 3437)DDPKLYDKDLGSAMGDWVVGWLDAAWSL (SEQ ID NO: 3438)DDPKLYDKDLGSAMGDWVVGWLMDAATSL$ (SEQ ID NO: 3439)DDPKLYDKDLGSAMGDWVVGWLDAATSL (SEQ ID NO: 3440)DDPKLYDKDLGSAMGDWVVGWMDAAWSL$ (SEQ ID NO: 3441)DDPKLYDKDLGSAMGDWVVGWMDAAWSL (SEQ ID NO: 3442)DDPKLYDKDLGSAMGDWVVGWMDAATSL$ (SEQ ID NO: 3443)DDPKLYDKDLGSAMGDWVVGWMDAATSL (SEQ ID NO: 3444)DDPKLYDKDLGSAMGDWVVGQVDAAWSL$ (SEQ ID NO: 3445)DDPKLYDKDLGSAMGDWVVGQVDAAWSL (SEQ ID NO: 3446)DDPKLYDKDLGSAMGDWVVGQVDAATSL$ (SEQ ID NO: 3447)DDPKLYDKDLGSAMGDWVVGQVDAATSL (SEQ ID NO: 3448)DDPKLYDKDLGSAMGDWVVGQLDAAWSL$ (SEQ ID NO: 3449)DDPKLYDKDLGSAMGDWVVGQLDAAWSL (SEQ ID NO: 3450)DDPKLYDKDLGSAMGDWVVGQLDAATSL$ (SEQ ID NO: 3451)DDPKLYDKDLGSAMGDWVVGQLDAATSL (SEQ ID NO: 3452)DDPKLYDKDLGSAMGDWVVGQMDAAWSL$ (SEQ ID NO: 3453)DDPKLYDKDLGSAMGDWVVGQMDAAWSL (SEQ ID NO: 3454)DDPKLYDKDLGSAMGDWVVGQMDAATSL$ (SEQ ID NO: 3455)DDPKLYDKDLGSAMGDWVVGQMDAATSL (SEQ ID NO: 3456)DDPKLYDKDLGSAMGDTVVAQLDAAWSL$ (SEQ ID NO: 3457)DDPKLYDKDLGSAMGDTVVAQLDAAWSL (SEQ ID NO: 3458)DDPKLYDKDLGSAMGDTVVAQLDAATSL$ (SEQ ID NO: 3459)DDPKLYDKDLGSAMGDTVVAQLDAATSL (SEQ ID NO: 3460)DDPKLYDKDLGSAMGDTVVGQMDAAWSL$ (SEQ ID NO: 3461)DDPKLYDKDLGSAMGDTVVGQMDAAWSL (SEQ ID NO: 3462)DDPKLYDKDLGSAMGDTVVGQMDAATSL$ (SEQ ID NO: 3463)DDPKLYDKDLGSAMGDTVVGQMDAATSL (SEQ ID NO: 3464)DDPKLYDKDLGSAMGDTVVAWMDAAWSL$ (SEQ ID NO: 3465)DDPKLYDKDLGSAMGDTVVAWMDAAWSL (SEQ ID NO: 3466)DDPKLYDKDLGSAMGDTVVAWMDAATSL$ (SEQ ID NO: 3467)DDPKLYDKDLGSAMGDTVVAWMDAATSL (SEQ ID NO: 3468)DDPKLYDKDLGSAMGDTVVAQVDAAWSL$ (SEQ ID NO: 3469)DDPKLYDKDLGSAMGDTVVAQVDAAWSL (SEQ ID NO: 3470)DDPKLYDKDLGSAMGDTVVAQVDAATSL$ (SEQ ID NO: 3471)DDPKLYDKDLGSAMGDTVVAQVDAATSL (SEQ ID NO: 3472)DDPKLYDKDLGSAMGDTVVAQLDAAWSL$ (SEQ ID NO: 3473)DDPKLYDKDLGSAMGDTVVAQLDAAWSL (SEQ ID NO: 3474)DDPKLYDKDLGSAMGDTVVAQLDAATSL$ (SEQ ID NO: 3475)DDPKLYDKDLGSAMGDTVVAQLDAATSL (SEQ ID NO: 3476)DDPKLYDKDLGSAMGDTVVAQMDAAWSL$ (SEQ ID NO: 3477)DDPKLYDKDLGSAMGDTVVAQMDAAWSL (SEQ ID NO: 3478)DDPKLYDKDLGSAMGDTVVAQMDAATSL$ (SEQ ID NO: 3479)DDPKLYDKDLGSAMGDTVVAQMDAATSL (SEQ ID NO: 3480)DDPKLYDKDLGSAMGDTVVGWVDAAWSL$ (SEQ ID NO: 3481)DDPKLYDKDLGSAMGDTVVGWVDAAWSL (SEQ ID NO: 3482)DDPKLYDKDLGSAMGDTVVGWVDAATSL$ (SEQ ID NO: 3483)DDPKLYDKDLGSAMGDTVVGWVDAATSL (SEQ ID NO: 3484)DDPKLYDKDLGSAMGDTVVGWLDAAWSL$ (SEQ ID NO: 3485)DDPKLYDKDLGSAMGDTVVGWLDAAWSL (SEQ ID NO: 3486)DDPKLYDKDLGSAMGDTVVGWLDAATSL$ (SEQ ID NO: 3487)DDPKLYDKDLGSAMGDTVVGWLDAATSL (SEQ ID NO: 3488)DDPKLYDKDLGSAMGDTVVGQMDAAWSL$ (SEQ ID NO: 3489)DDPKLYDKDLGSAMGDTVVGQMDAAWSL (SEQ ID NO: 3490)DDPKLYDKDLGSAMGDTVVGQMDAATSL$ (SEQ ID NO: 3491)DDPKLYDKDLGSAMGDTVVGQMDAATSL (SEQ ID NO: 3492)DDPKLYDKDLGSAMGDTVVGQMDAAWSL$ (SEQ ID NO: 3493)DDPKLYDKDLGSAMGDTVVGQMDAAWSL (SEQ ID NO: 3494)DDPKLYDKDLGSAMGDTVVGQMDAATSL$ (SEQ ID NO: 3495)DDPKLYDKDLGSAMGDTVVGQMDAATSL (SEQ ID NO: 3496)DDPKLYDKDLGSAMGDTVVGQMDAAWSL$ (SEQ ID NO: 3497)DDPKLYDKDLGSAMGDTVVGQMDAAWSL (SEQ ID NO: 3498)DDPKLYDKDLGSAMGDTVVGQMDAATSL$ (SEQ ID NO: 3499)DDPKLYDKDLGSAMGDTVVGQMDAATSL (SEQ ID NO: 3500)DDPKLYDKDLGSAMGDTVVGQMDAAWSL$ (SEQ ID NO: 3501)DDPKLYDKDLGSAMGDTVVGQMDAAWSL (SEQ ID NO: 3502)DDPKLYDKDLGSAMGDTVVGQMDAATSL$ (SEQ ID NO: 3503)DDPKLYDKDLGSAMGDTVVGQMDAATSL (SEQ ID NO: 3504) * is acetylated $ isamidated

PEGylation

Covalent attachment of PEG to drugs of therapeutic and diagnosticimportance has extended the plasma half-life of the drug in vivo, and/orreduced their immunogenicity and antigenicity. Harris and Chess, NatureReviews Drug Discovery 2:214-221 (2003). For example, PEG attachment hasimproved the pharmacokinetic properties of many therapeutic proteins,including interleukins (Kaufman et al., 3. Biol. Chem. 263:15064 (1988);Tsutsumi et al., J. Controlled Release 33:447 (1995)), interferons (Kitaet al., Drug Des Delivery 6:157 (1990)), catalase (Abuchowski et al., J.Biol. Chem. 252:3582 (1977)), superoxide dismutase (Beauchamp et al.,Anal. Biochem. 131:25 (1983)), and adenosine deaminase (Chen et al.,Biochem. Biophys. Acta 660:293 (1981)), among others. The FDA hasapproved PEG for use as a vehicle or base in foods, cosmetics andpharmaceuticals, including injectable, topical, rectal and nasalformulations. PEG shows little toxicity, and is eliminated from the bodyintact by either the kidneys (for PEGs<30 kDa) or in the feces (forPEGs>20 kDa). PEG is highly soluble in water.

PEGylation of a therapeutic peptide may be used U increase the lifetimeof the peptide in the bloodstream of the patient by reducing renalultrafiltration, and thus reduce elimination of the drug from the body.Charge masking may affect renal permeation. Charge masking may be aconsequence of the paramchemical modification of protein ionizablefunctional group, namely amines or carboxyls. In particular, the mostcommon procedures for producing protein-PEG derivatives involves theconversion of protein amino groups into amides with the consequent lossof positive charges, and this can alter protein ultrafiltration. Sinceanionic macromolecules have been found to be cleared by renalultrafiltration more slowly than neutral or positive ones, it could beexpected that PEG conjugation to amino groups prolongs the permanence ofthe PEGylated peptide in the bloodstream.

Molecular size and globular ultrafiltration may also affect renalultrafiltration of therapeutic peptides. The molecular weight cut offfor kidney elimination of native globular proteins is considered to beabout 70 kDa, which is close to the molecular weight of serum albumin.Thus, proteins with molecular weight exceeding 70 kDa are mainlyeliminated from the body by pathways other than renal ultrafiltration,such as liver uptake, proteolytic digestion and clearance by the immunesystem. Therefore, increasing the size of a therapeutic peptide byPEGylation may decrease renal ultrafiltration of that peptide form thebloodstream of the patient.

Additionally, PEGylation of a therapeutic peptide may decrease theimmunogenicity of that peptide, as well as protect the peptide fromproteolytic enzymes, phagocytic cells, and other factors that requiredirect contact with the therapeutic peptide. The umbrella-like structureof branched PEG in particular has been found to give better protectionthan linear PEG towards approaching proteolytic enzymes, antibodies,phagocytic cells, etc. Caliceti and Veronese, Adv. Drug. Deliv. Rev.55:1261-12778 (2003).

In some embodiments, the cupredoxin derived peptides are modified tohave one or more PEG molecules covalently bonded to a cysteine molecule.The covalent bonding docs not necessarily need to be a covalent bonddirectly from the PEG molecule to the cupredoxin derived peptide, butmay be covalently bonded to one or more linker molecules which in turnare covalently bonded to each other and/or the cupredoxin derivedpeptide. In some embodiments, the cupredoxin derived peptide havesite-specific PEGylation. In specific embodiments, the PEG molecule(s)may be covalently bonded to the cysteine residues 3, 26 and/or 112 of P.aeruginosa azurin (SEQ ID NO: 1). In other embodiments, one or morecysteine residues may be substituted into the cupredoxin derived peptideand is PEGylated. In some embodiments, the method to PEGylate thecupredoxin derived peptide may be NHS, reductive animation, malimid orepoxid, among others. In other embodiments, the cupredoxin derivedpeptides may be PEGylated on one or more lysine, cysteine, histidine,arginine, aspartic acid, glutamic acid, serine, threonine, or tyrosine,or the N-terminal amino group or the C-terminal carboxylic acid. In morespecific embodiments, the cupredoxin derived peptides may be PEGylatedon one or more lysines or N-terminal amino groups. In other embodiments,one or more lysine, cysteine, histidine, arginine, aspartic acid,glutamic acid, serine, threonine, or tyrosine residue are substitutedinto the cupredoxin derived peptides and are PEGylated. In otherembodiments, the cupredoxin derived peptides may be PEGylated on one ormore amino groups. In other embodiments, the cupredoxin derived peptidesmay be PEGylated in a random, non-site specific manner. In someembodiments, the cupredoxin derived peptides may have an averagemolecular weight of PEG-based polymers of about 200 daltons to about100,000 daltons, about 2,000 daltons to about 20,000 daltons, or about2,000 daltons to about 5,000 daltons. In other embodiments, thecupredoxin derived peptides may be comprised of one or more PEGmolecules that is branched, specifically a branched PEG molecule that isabout 50 kDa. In other embodiments, the cupredoxin derived peptides maycomprise one or more linear PEG molecules, specifically a linear PEGmolecule that is about 5 kDa.

Cupredoxin

“Cupredoxins” are small blue copper containing proteins having electrontransfer properties (10-20 kDa) that participate in, for example,bacterial redox chains or photosynthesis. The copper ion is solely boundby the protein matrix. A special distorted trigonal planar arrangementto two histidine and one cysteinate ligands around the copper gives riseto very peculiar electronic properties of the metal site and an intenseblue color. A number of cupredoxins have been crystallographicallycharacterized at medium to high resolution. The cupredoxins include theazurins, plastocyanins, rusticyanins, pseudoazurins, auracyanins andazurin-like proteins. As used herein, the term “cupredoxin” includes theprotein form without the copper atom present, as well as the coppercontaining protein.

Azurins

The azurins are copper containing proteins of 128 amino acid residueswhich belong to the family of cupredoxins involved in electron transferin plants and certain bacteria. The azurins include those from P.aeruginosa (SEQ ID NO: 1)(“wt-azurin”), A. xylosoxidans, mid A.denitrificans. Murphy et al., J. Mol. Biol. 315:859-871 (2002). Althoughthe sequence homology between the azurins varies between 60-90%, thestructural homology between these molecules is high. AH azurins have acharacteristic β-sandwich with Greek key motif and the single copperatom is always placed at the same region of the protein. In addition,azurins possess an essentially neutral hydrophobic patch surrounding thecopper site. Id.

Plastocyanins

The plastocyanins are cupredoxins that are found in eukaryotic plantsand cyanobacteria. They contain one molecule of copper per molecule andare blue in their oxidized form. They occur in the chloroplast, wherethey function as electron carriers. Since the determination of thestructure of poplar plastocyanin in 1978, the structure of algal(Scenedesmus, Enteromorpha, Chlamydomonas) and plant (French bean)plastocyanins has been determined either by crystallographic or NMRmethods, and the poplar structure has been refined to 1.33 Å resolution.SEQ ID NO: 2 shows the amino acid sequence of plastocyanin from thecyanobacterium Phormidium laminosum.

Despite the sequence divergence among plastocyanins of algae andvascular plants (e.g., 62% sequence identity between the Chlamydomonasand poplar proteins), the three-dimensional structures are conserved(e.g., 0.76 Å rms deviation in the C alpha positions between theChlamydomonas and Poplar proteins). Structural features include adistorted tetrahedral copper binding site at one end of aneight-stranded antiparallel beta-barrel, a pronounced negative patch,and a flat hydrophobic surface. The copper site is optimized for itselectron transfer function, and the negative and hydrophobic patches areproposed to be involved in recognition of physiological reactionpartners. Chemical modification, cross-linking, and site-directedmutagenesis experiments have confirmed the importance of the negativeand hydrophobic patches in binding interactions with cytochrome f, andvalidated the model of two functionally significant electron transferpaths in plastocyanin. One putative electron transfer path is relativelyshort, (approximately 4 Å) and involves the sol vent-exposed copperligand His-87 in the hydrophobic patch, while the other is more lengthy(approximately 12-15 Å) and involves the nearly conserved residue Tyr-83in the negative patch. Redinbo et al., J. Bioenerg. Biomembr.26(1):49-66 (1994).

Rusticyanins

Rusticyanins are blue-copper containing single-chain polypeptidesobtained from a thiobacillus. The X-ray crystal structure of theoxidized form of the extremely stable and highly oxidizing cupredoxinrusticyanin from Thiobacillus ferrooxidans (SEQ ID NO; 3) has beendetermined by multiwavelength anomalous diffraction and refined to 1.9 Åresolution. The rusticyanins are composed of a core beta-sandwich foldcomposed of a six- and a seven-stranded β-sheet. Like other cupredoxins,the copper ion is coordinated by a cluster of four conserved residues(His 85, Cys138, His143, Met148) arranged in a distorted tetrahedron.Walter et al., J. Mol. Biol. 263:730-51 (1996).

Auracyanins

Three small blue copper proteins designated auracyanin A, auracyanin B1, and auracyanin B-2 have been isolated from the thermophilic greengliding photosynthetic bacterium Chloroflexus aurantiacus. The two Bforms have almost identical properties to each other, but are distinctfrom the A form. The sodium dodecyl sulfate-polyacrylamide gelelectrophoresis demonstrates apparent monomer molecular masses as 14(A), 18 (B-2), and 22 (B-1) kDa.

The amino acid sequence of auracyanin A has been determined and showedauracyanin A to be a polypeptide of 139 residues. Van Dreissche et al,Protein Science 8:947-957 (1999). His58, Cys123, His128, and Met132 arespaced in a way to be expected if they are the evolutionary conservedmetal ligands as in the known small copper proteins plastocyanin andazurin. Secondary structure prediction also indicates that auracyaninhas a general beta-barrel structure similar to that of azurin fromPseudomonas aeruginosa and plastocyanin from poplar leaves However,auracyanin appears to have sequence characteristics of both small copperprotein sequence classes. The overall similarity with a consensussequence of azurin is roughly the same as that with a consensus sequenceof plastocyanin, namely 30-5%. The N-terminal sequence region 1-18 ofauracyanin is remarkably rich in glycine and hydroxy amino acids. Id Seeexemplary amino acid sequence SEQ ID NO; 10 for chain A of auracyaninfrom Chloroflexus aurantiacus (NCBI Protein Data Bank Accession No.AAM12874).

The auracyanin B molecule has a standard cupredoxin fold. The crystalstructure of auracyanin B from Chloroflexus aurantiacus has beenstudied. Bond et al., J. Mol. Biol. 306:47-67 (2001). With the exceptionof an additional N-terminal strand, the molecule is very similar to thatof the bacterial cupredoxin, azurin. As in other cupredoxins, one of theCu ligands lies on strand 4 of the polypeptide, and the other three liealong a large loop between strands 7 and 8. The Cu site geometry isdiscussed with reference to the amino acid spacing between the latterthree ligands. The crystallographically characterized Cu-binding domainof auracyanin B is probably tethered to the periplasmic side of thecytoplasmic membrane by an N-terminal tail that exhibits significantsequence identity with known tethers in several othermembrane-associated electron-transfer proteins. The amino acid sequencesof the B forms are presented in McManus et al., (J Biol Chem.267:6531-6540(1992)). See exemplary amino acid sequence SEQ ID NO: 11for chain A of auracyanin B from Chloroflexus aurantiacus (NCBI ProteinData Bank Accession No. 1QHQA).

Pseudoazurins

The pseudoazurins are a family of blue-copper containing single-chainpolypeptides. The amino acid sequence of pseudoazurin obtained fromAchromobacter cycloclastes is shown in SEQ ID NO: 4. The X-ray structureanalysis of pseudoazurin shows that it has a similar structure to theazurins although there is low sequence homology between these proteins.Two main differences exist between the overall structure of thepseudoazurins and azurins. There is a carboxy terminus extension in thepseudoazurins, relative to the azurins, consisting of two alpha-helices.In the mid-peptide region azurins contain an extended loop, shortened inthe pseudoazurins, which forms a flap containing a short α-helix. Theonly major differences at the copper atom site are the conformation ofthe MET side-chain and the Met-S copper bond length, which issignificantly shorter in pseudoazurin than in azurin.

The modified cupredoxin derived peptides may be synthesized by standardtechniques. Variants are amino acid sequences formed from nativecompounds either directly or by modification or partial substitution.Changes may be introduced into a cupredoxin derived peptide that incuralterations in the amino acid sequences of the cupredoxin derivedpeptide that do nullify the pharmacologic activity(ies) of thecupredoxin. A “non-essential” amino acid residue is a residue that canbe altered from the sequence of the cupredoxin derived peptide withoutnullifying its pharmacologic activity, whereas an “essential” amino acidresidue is required for such pharmacologic activity.

Amino acids for which “conservative” substitutions can be made are wellknown in the art. Useful conservative substitutions are shown in Table1, “Preferred substitutions.” Conservative substitutions whereby anamino acid of one class is replaced with another amino acid of the sameclass fall within the scope of the invention so long as the substitutiondoes not nullify the desired pharmacologic activity of the cupredoxinderived peptide. Such exchanges that result in altered cupredoxinderived pharmacologic activity are contemplated as pan of the inventionso long as such pharmacologic activity is appreciable. In someembodiments, the pharmacologic activity of the cupredoxin derivedpeptide is less that about 5%, less than about 10%, less man about 25%and less than about 50% of the specific activity of the wild typecupredoxin from which it is derived. It will be appreciated that someloss of specific activity of the cupredoxin derived peptide may betolerated if it is offset by other improved qualities in the cupredoxinderived peptide, such as longer plasma half-life or decreasedimmunogenicity.

TABLE 1 Preferred substitutions Preferred Original residue Exemplarysubstitutions substitutions Ala (A) Val, Leu, Ile Val Arg (R) Lys, Gln,Asn Lys Asn (N) Gln, His, Lys, Arg Gln Asp (D) Glu Glu Cys (C) Ser SerGln (Q) Asn Asn Glu (E) Asp Asp Gly (G) Pro, Ala Ala His (H) Asn, Gln,Lys, Arg Arg Ile (I) Leu, Val, Met, Ala, Phe, Leu Norleucine Leu (L)Norleucine, Ile, Val, Met, Ala, Ile Phe Lys (K) Arg, Gln, Asn Arg Met(M) Leu, Phe, Ile Leu Phe (F) Leu, Val, Ile, Ala, Tyr Leu Pro (P) AlaAla Ser (S) Thr Thr Thr (T) Ser Ser Trp (W) Tyr, Phe Tyr Tyr (Y) Trp,Phe, Thr, Ser Phe Val (V) Ile, Leu, Met, Phe, Ala, Leu Norleucine

“Non-conservative” substitutions that affect (1) the structure of thepolypeptide backbone, such as a β-sheet or α-helical conformation, (2)the charge, (3) hydrophobicity, or (4) the bulk of the side chain canmodify pharmacologic activity of a cupredoxin derived peptide. Residuesare divided into groups based on common side-chain properties as denotedin Table 2. Non-conservative substitutions entail exchanging a member ofone of these classes for another class.

Non-conservative substitutions whereby an amino acid of one class isreplaced with another amino acid of a different class fail within thescope of the invention so long as the substitution does not nullify thepharmacologic activity of the cupredoxin derived peptide. Such exchangesthat result in altered cupredoxin derived peptide pharmacologic activityare contemplated as part of the invention so long as such pharmacologicactivity is appreciable.

TABLE 2 Amino acid classes Class Amino acids hydrophobic Norleucine,Mer, Ala, Val, Leu, Ile neutral hydrophilic Cys, Ser, Thr acidic Asp,Glu basic Asn, Gln, His, Lys, Arg disrupt chain Gly, Pro conformationaromatic Trp, Tyr, Phe

Modifications to the cupredoxin derived peptide can be made usingmethods known in the art such as oligonucleotide-mediated(site-directed) mutagenesis, alanine scanning, and PCR mutagenesis.Site-directed mutagenesis (Carter, Biochem J. 237:1-7 (1986); Zoller andSmith, Methods Enzymol. 154:329-50 (1987)), cassette mutagenesis,restriction selection mutagenesis (Wells et al., Gene 34:315-23 (1985))or other known techniques can be performed on the cloned DNA to producea cupredoxin derived peptide encoding variant nucleic acid. In addition,nucleotides encoding a cupredoxin derived peptide that is a structuralequivalent of a cupredoxin may be synthesized by methods that are wellknown in the art. Further, protein molecules that are modifiedcupredoxin derived peptide may be synthesized by methods that are wellknown in the art.

Nucleic Acids Coding for a Cupredoxin Entry Domain and Complex of aCupredoxin Entry Domain Linked to a Cargo Compound

In another aspect, the present invention provides a nucleic acidmolecule encoding a modified cupredoxin derived peptide of theinvention. This nucleic acid molecule can be prepared by a combinationof known techniques in the art. For instance, nucleic acid sequences forthe modified cupredoxin derived peptide can individually be prepared bychemical synthesis or cloning.

Hybrid Systems Comprising a Cupredoxin, Modified Cupredoxin, or ModifiedCupredoxin-Derived Peptide and a Nanoparticle

In another aspect, the present invention provides a biological moleculethat is a cupredoxin, such as P. aeruginosa azurin (SEQ ID NO: 1),and/or a cupredoxin-derived peptide, which may be modified using one ormore of the methods or techniques disclosed herein, conjugated with ananoparticle, which may be a noble metal such as gold or platinum. Thebiological molecule may be conjugated to the nanoparticle via electronicinteractions or other means. Specifically, conjugation may be viaelectron transfer. See Delfino, I and Cannistraro, S., “Opticalinvestigation of the electron transfer protein azurin-gold nanoparticlesystem,” Biophysical Chemistry 139 (2009) 1-7 (available online 30 Sep.2008), the disclosure of which is incorporated by reference in itsentirety herein.

In some embodiments, hybrid systems comprising a modifiedcupredoxin-derived peptide and a nanoparticle may be used for purposesof imaging, diagnostics, and/or cancer therapy.

Pharmaceutical Compositions Containing Modified Cupredoxin DerivedPeptides

Pharmaceutical compositions containing a modified cupredoxin derivedpeptide can be manufactured in any conventional manner, e.g., byconventional mixing, dissolving, granulating, dragee-making,emulsifying, encapsulating, entrapping, or lyophilizing processes. Themodified cupredoxin derived peptide can be readily combined with apharmaceutically acceptable carrier well-known in the art-Such carriersenable the preparation to be formulated as a tablet, pill, dragee,capsule, liquid, gel, syrup, slurry, suspension, and the like. Suitableexcipients can also include, for example, fillers and cellulosepreparations. Other excipients can include, for example, flavoringagents, coloring agents, detackifiers, thickeners, and other acceptableadditives, adjuvants, or binders.

Such compositions can be used in, for example, the treatment ordiagnosis of cancer, treatment of inappropriate angiogenesis, infectionby HIV and/or malaria, and treatment of conditions related toephrin-signaling. The compositions can be administered in an amountsufficient to prevent or treat the condition from which the patient issuffering. Typically, the patient organism is a mammal, such as a humanor animal.

Administration of Compositions Containing a Cupredoxin Entry Domain

Compositions containing a modified cupredoxin derived peptide can beadministered by any suitable route, for example, by oral, buccal,inhalation, sublingual, rectal, vagina), transurethral, nasal, topical,percutaneous, i.e., transdermal or parenteral (including intravenous,intramuscular, subcutaneous and intracoronary administration). Thecompositions and pharmaceutical formulations thereof can be administeredin any amount effective to achieve its intended purpose. Whenadministrated to treat a patient suffering from a condition, thecomposition is administered in a therapeutically effective amount. A“therapeutically effective amount” is an amount effective to preventdevelopment of, or to alleviate the existing symptoms of, the subjectbeing treated. Determination of a therapeutically effective amount iswell within the capability of those skilled in the art.

In various embodiments, the composition includes carriers and excipients(including but not limited to buffers, carbohydrates, mannitol,proteins, polypeptides or amino acids such as glycine, antioxidants,bacteriostats, chelating agents, suspending agents, thickening agentsand/or preservatives), water, oils, saline solutions, aqueous dextroseand glycerol solutions, other pharmaceutically acceptable auxiliarysubstances as required to approximate pharmacologic conditions, such asbuffering agents, tonicity adjusting agents, wetting agents and thelike. It will be recognized that, while any suitable carrier known tothose of ordinary skill in the art may be employed to administer thecompositions of this invention, the type of carrier will vary dependingon the mode of administration. Compounds may also be encapsulated withinliposomes using well-known technology. Biodegradable microspheres mayalso be employed as carriers for the compositions of thisinvention-Suitable biodegradable microspheres are shown, for example, inU.S. Pat. Nos. 4,897,268, 5,075,109, 5,928,647, 5,811,128, 5,820,883,5,853,763, 5,814,344 and 5,942,252. “Compounds” as used herein, includethe peptides, amino acid sequences, cargo compounds and complexes of thepresent invention.

The compositions of the invention may be sterilized by conventional,well-known sterilization techniques, or may be sterile filtered. Theresulting aqueous solutions may be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterilesolution prior to administration.

The compositions of the invention may be administered in a variety ofways, including by injection (e.g., intradermal, subcutaneous,intramuscular, intraperitoneal and the like), by inhalation, by topicaladministration, by suppository, by using a transdermal patch or bymouth.

When administration is by injection, composition may be formulated inaqueous solutions, preferably in physiologically compatible buffers suchas Hanks solution. Ringer's solution, or physiological saline buffer.The solution may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the composition maybe in powder form for constitution with a suitable vehicle, e.g.,sterile pyrogen-free water, before use.

When administration is by inhalation, the composition may be deliveredin the form of an aerosol spray from pressurized packs or a nebulizerwith the use of a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, carbon dioxide or other suitable gas. In thecase of a pressurised aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, e.g., gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of the proteins and a suitable powder base suchas lactose or starch.

When administration is by topical administration, the composition may beformulated as solutions, gels, ointments, creams, suspensions, and thelike, as are welt known in the art. In some embodiments, administrationis by means of a transdermal patch. When administration is bysuppository (e.g., rectal or vaginal), composition may also beformulated in compositions containing conventional suppository bases.

When administration is oral, the composition can be readily formulatedin combination with pharmaceutically acceptable carriers well known inthe art. A solid carrier, such as mannitol, lactose, magnesium stearate,and the like may be employed; such carriers enable the chemotaxin to beformulated as tablets, pills, dragees, capsules, liquids, gels, syrups,slurries, suspensions and the like, for oral ingestion by a subject tobe treated. For oral solid formulations such as, for example, powders,capsules and tablets, suitable excipients include fillers such assugars, cellulose preparation, granulating agents, and binding agents.

Other convenient carriers, as well-known in the art, also includemultivalent carriers, such as bacterial capsular polysaccharide, adextran or a genetically engineered vector. In addition,sustained-release formulations that include the composition allow forthe release of the composition over extended periods of time, such thatwithout the sustained release formulation, composition would be clearedfrom a subject's system, and/or degraded by, for example, proteases andsimple hydrolysis before eliciting or enhancing an therapeutic effect.

The exact formulation, route of administration, and dosage is typicallydetermined by the attending physician in view of the patient'scondition. Dosage amount and interval can be adjusted individually toprovide plasma levels of the complex which are sufficient to maintaintherapeutic effect. Generally, the desired composition is administeredin an admixture with a pharmaceutical carrier selected with regard tothe intended route of administration and standard pharmaceuticalpractice.

The appropriate dosage will, of course, vary depending upon, forexample, the compound containing the cupredoxin entry domain employed,the host, the mode of administration and the nature and severity of theconditions being treated or diagnosed. However, in one embodiment of themethods of the present invention, satisfactory treatment results inhumans are indicated to be obtained at daily dosages from about 0.001 toabout 20 mg/kg of body weight of the compound containing the modifiedcupredoxin derived peptide. In one embodiment, an indicated daily dosagefor treatment in humans may be in the range from about 0.7 mg to about1400 mg of a compound containing the modified cupredoxin derived peptideconveniently administered, for example, in daily doses, weekly doses,monthly doses, and/or continuous dosing. Daily doses can be in discretedosages from 1 to 12 times per day. Alternatively, doses can beadministered every other day, every third day, every fourth day, everyfifth day, every sixth day, every week, and similarly in day incrementsup to 31 days. Dosing can be continuous, intermittent or a single dose,using any applicable dosing form, including tablet, patches, i.v.administration and the like. More specifically, the composition isadministered in a therapeutically effective amount. In specificembodiments, the therapeutically effective amount is from about 0.01-20mg/kg of body weight. In specific embodiments, the dose level is about10 mg/kg/day, about 15 mg/kg/day, about 7-0 mg/kg/day, about 25mg/kg/day, about 30 mg/kg/day, about 35 mg/kg/day, about 40 mg/kg/day,about 45 mg/kg/day or about 50 mg/kg/day.

The method of introducing compounds containing the modified cupredoxinderived peptide to patients is, in some embodiments, co-administrationwith other drugs known to treat the condition. Such methods arewell-known in the art. In a specific embodiment, the compoundscontaining the modified cupredoxin derived peptide are part of ancocktail or co-dosing containing or with other drugs for treatingcancer, HIV, malaria, inappropriate angiogenesis, and conditions relatedto ephrin-signaling. Many other such compounds are known to thoseskilled in the art and are provided by the patent applications that havebeen expressly incorporated by reference.

Nucleic acid molecules encoding a cupredoxin derived peptide or a fusionprotein combining a cupredoxin derived peptide and a cargo compound canbe inserted into vectors and used as gene therapy vectors. Gene therapyvectors can be delivered to a subject by, for example, intravenousinjection, local administration (Nabel et al., U.S. Pat. No. 5,328,470),or by stereotactic injection (Chen et al., Proc Natl Acad Sci USA91:3054-3057 (1994)). The pharmaceutical preparation of a gene therapyvector can include an acceptable diluent or can comprise a slow releasematrix in which the gene delivery vehicle is imbedded. Alternatively,where the complete gene delivery vector can be produced intact fromrecombinant cells, e.g., retroviral vectors, the pharmaceuticalpreparation can include one or more cells that produce the gene deliverysystem.

In one aspect, the composition is delivered as DNA such that the complexis generated in situ. In one embodiment, the DNA is “naked,” asdescribed, for example, in Ulmer et al., Science 259:1745-1749 (1993)and reviewed by Cohen, Science 259 1691-1692 (1993). The uptake of nakedDNA may be increased by coating the DNA onto a carrier, e.g. abiodegradable bead, which is efficiently transported into the cells. Insuch methods, the DNA may be present within any of a variety of deliverysystems known to those of ordinary skill in the art, including nucleicacid expression systems, bacterial and viral expression systems.Techniques for incorporating DNA into such expression systems are wellknown to those of ordinary skill in the art. See, e.g., WO90/11092,WO93/24640, WO 93/17706, and U.S. Pat. No. 5,736,524.

Vectors, used to shuttle genetic material from organism to organism, canbe divided into two general classes: Cloning vectors are replicatingplasmid or phage with regions that are non-essential fox propagation inan appropriate host cell and into which foreign DNA can be inserted; theforeign DNA is replicated and propagated as if it were a component ofthe vector. An expression vector (such as a plasmid, yeast, or animalvirus genome) is used to introduce foreign genetic material into a hostcell or tissue in order to transcribe and translate the foreign DNA,such as the DNA of the composition. In expression vectors, theintroduced DNA is operably-linked to elements such as promoters thatsignal to the host cell to transcribe the inserted DNA. Some promotersare exceptionally useful, such as inducible promoters that control genetranscription in response to specific factors. Operably-linking acomposition polynucleotide to an inducible promoter can control theexpression of a modified cupredoxin derived peptide of the invention.Examples of classic inducible promoters include those that areresponsive to α-interferon, heat shock, heavy metal ions, and steroidssuch as glucocorticoids (Kaufman, Methods Enzymol. 185:487-511 (1990))and tetracycline. Other desirable inducible promoters include those thatare not endogenous to the cells in which the construct is beingintroduced, but, however, are responsive in those cells when theinduction agent is exogenously supplied. In general, useful expressionvectors are often plasmids. However, other forms of expression vectors,such as viral vectors (e.g., replication defective retroviruses,adenoviruses and adeno-associated viruses) are contemplated.

Vector choice is dictated by the organism or cells being used and thedesired fate of the vector. In general, vectors comprise signalsequences, origins of replication, marker genes, enhancer elements,promoters, and transcription termination sequences.

Kits Comprising a Modified Cupredoxin Derived Peptide

In another aspect, the invention provides kits containing one or more ofthe following in a package or container; (1) a reagent comprising amodified cupredoxin derived peptide; (2) a reagent containing apharmaceutically acceptable adjuvant or excipient; (3) a vehicle foradministration, such as a syringe; and (4) instructions foradministration. Embodiments in which two or more of components (1)-(4)are found in the same container are also contemplated.

When a kit is supplied, the different components of the composition maybe packaged in separate containers and admixed immediately before use.Such packaging of the components separately may permit long-term storagewithout losing the active components' functions.

The reagents included in the kit can be supplied in containers of anyson such that the life of the different components are preserved and arenot adsorbed or altered by the materials of the container. For example,sealed glass ampules may contain lyophilized polypeptide orpolynucleotide, or buffers that have been packaged under a neutral,non-reacting gas, such as nitrogen Ampules may consist of any suitablematerial, such as glass, organic polymers, such as polycarbonate,polystyrene, etc., ceramic, metal or any other material typicallyemployed to hold similar reagents. Other examples of suitable containersinclude simple bottles that may be fabricated from similar substances asampules, and envelopes, that may comprise foil-lined interiors, such asaluminum or an alloy. Other containers include test tubes, vials,flasks, bottles, syringes, or the like. Containers may have a sterileaccess port, such as a bottle having a stopper that can be pierced by ahypodermic injection needle. Other containers may have two compartmentsthat are separated by a readily removable membrane that upon removalpermits the components to be mixed. Removable membranes may be glass,plastic, rubber, etc.

Kits may also be supplied with instructional materials. Instructions maybe printed on paper or other substrate, and/or may be supplied as anelectronic-readable medium, such as a floppy disc, CD-ROM, DVD-ROM, Zipdisc, videotape, audiotape, flash memory device, etc. Detailedinstructions may not be physically associated with the kit; instead, auser may be directed to an internet web site specified by themanufacturer or distributor of the kit, or supplied as electronic mail.

A more complete understanding of the present invention can be obtainedby reference to the following specific Examples. The Examples aredescribed solely for purposes of illustration and are not intended tolimit the scope of the invention. Changes in form and substitution ofequivalents are contemplated as circumstances may suggest or renderexpedient. Although specific terms have been employed herein, such termsare intended in a descriptive sense and not for purposes of limitations.Modifications and variations of the invention as hereinbefore set forthcan be made without departing from the spirit and scope thereof, and,therefore, only such limitations should be imposed as are indicated bythe appended embodiments.

EXAMPLES Example 1—Treatment of Patients Suffering from Cancer withModified Cupredoxin Derived Peptides

A Phase I/II clinical trial of a thioether cyclized p28 (SEQ ID NO: 13)fusion (Study Drug) will be performed in patients suffering from cancer.Specifically, p28 (SEQ ID NO: 13) from Pseudomonas aeruginosa will bemodified by thioether cyclization.

Forty-nine adult patients with histologically verified cancers of thebreast, colon and melanoma who demonstrate clinical and radiographicprogression or recurrence following adequate treatment by currentlyavailable FDA-approved chemotherapeutic drugs and regimen will beenrolled in an open-label prospective study administering the StudyDrug. To be eligible for enrollment in the study, all patientsdemonstrate increasing volume of measurable tumor after completion ofapproved course of chemotherapy regimens. The evidence of persistentmetastatic deposits and/or continued increase in size or volume must behistologically established. This histological proof can be obtained by afine needle aspiration (FNA) biopsy.

The treatment program will be instituted after obtaining informedconsent from all patients in accordance with the Institutional ReviewBoard of the University of Illinois, Chicago and the FDA. The patientswill have no intercurrent illness such as other malignancy, history ofprevious malignancy, blood dyscrasias, insulin dependent diabetes orother serious cardiovascular diseases which might interfere inappropriate evaluation of the effects of the proposed therapy. Baselineblood work (Complete Blood Counts [CBC] and Serum Chemistry) includingliver function studies (LFT) will be performed prior to initiation oftherapy. Ail eligible patients must not receive any cancer chemotherapyconcurrently during the period of the trial.

The study drug will be administered by daily intravenous injection of apharmaceutically acceptable preparation of the Study Drug for 12 weeksand the subjects will be observed for any dose limiting toxicity. Therewill be 7 dose levels starting with 10 mg/kg/day and increasing by 5mg/kg/day up to a maximum dose of 50 mg/kg/day. The efficacy of eachdose level will be recorded in 7 patients with advanced measurablecancer (breast, colon, and melanoma).

The response will be estimated by measuring the measurable tumor in 2dimensions (a and b). 1) Total disappearance of the target metastatictumors will be considered as complete response (CR); 2) A 75% reductionwill be considered excellent, partial response (PR); and 3) A goodresponse (PR) will be post treatment reduction in size by 50%. 4)Reduction of 25% in size will be considered as stable disease (SD) and5) 25% will be considered as no response (NR). Patients demonstrating aprogression of disease will have their treatment discontinued but willbe followed for an additional 12 weeks.

Total disappearance, and any reduction in size of the target metastatictumors will indicate mat the azurin treatment is effective for treatingcancer. Other indications that the thioether cyclized p28 (SEQ ID NO:13) treatment is effective are a decrease rate of in the appearance ofnew metastatic tumors and a decrease in the angiogenesis associated withtumors.

Various modifications and variations of the described examples andsystems of the invention will be apparent to those skilled in the artwithout departing from the scope and spirit of the invention. Althoughthe invention has been described in connection with specificembodiments, it should be understood that the invention as claimedshould not be unduly limited to such specific embodiments. Indeed,various modifications of the described modes for carrying out Uteinvention which are obvious to those skilled in related field; areintended to be within the scope of the following embodiments.

Example 2—Example 18—Entry of p18 (SEQ ID NO: 14) and p28 (SEQ ID NO:13) Into Human Cell Lines

Cell Culture and Cell Lines:

Human cancer and non-cancer (immortalized and non-immortalized) celllines were obtained from ATCC [lung cancer (A549 and NCI-H23adenocarcinoma), normal lung (CCD-13Lu), prostate cancers (DU145 andLN-CAP), normal prostate (CRL11611), breast cancer (MCP-7), normalbreast (MCF-10A), colon cancer (HCT116), normal colon (CCD33Co),fibrosarcoma (HT1080), and ovarian cancer (SK-OV3 adenocarcinoma)].Normal fibroblasts isolated from skin were established. Normal ovariancells (HOSE6-3) were donated by Dr. S. W. Tsao (University of HongKong). Melanoma lines (UISO-Mel-2, 23, 29) were established andcharacterized. All cells except UISO-Mel-2 were cultured in MEM-E(Invitrogen, Carlsbad, Calif.) supplemented with 10% heat-inactivatedfetal bovine serum (Atlanta Biological Inc., Lawrenceville, Ga.), 100units/ml penicillin and 100 μg/ml streptomycin at 37° C. in 5% CO2 orair.

Proliferation Assays/Cell Growth:

Melanoma cells were seeded (four replicates) in flat bottom 24 wellplates (Becton Dickinson, Franklin Lakes, N.J.) at a density of 12×103cells/well. After 24 hrs media was changed and fresh p18, p28 (SEQ IDNO: 13), azurin or a similar volume of media without peptide (eightreplicates) added daily for 72 hr. Cells were then counted in a BeckmanCoulter (Z 1 coulter particle counter). Values represent the mean SD of4 replicates.

MTT Assay:

Melanoma cells were seeded at a density of 2000 cells/well inflat-bottomed 96 well plates (Becton Dickinson, Franklin Lakes, N.J.)and allowed to attach for 24 hrs. Freshly prepared peptide (10 μl) orculture medium was then added to each well. After 24 hrs, medium waschanged and p18 (SEQ ID NO; 14), p28 (SEQ ID NO: 13) or azurin addeddaily. After 72 hr incubation, 10 μl of MIT reagent (Trevigen,Gaithersburg, Md.) was added to each well, the samples incubated for 3hr, RT/sig 100 μl of detergent added to each well, and the samplesincubated for an additional 3 hr at 37° C. Absorbance was measured witha SpectraMax 340 plate reader (Molecular Devices Corporation, Sunnyvale,Calif.) and percent change in the absorbance at 570 am in treated cellsrelative to untreated controls determined. Values represent the mean±SD.Significance between control and treated groups was determined byStudent's t-test.

Peptide Synthesis:

All azurin derived peptides including p18, Leu⁵⁰-Gly⁶⁷LSTAADMQGVVTDGMASG (SEQ ID NO: 14), p28 Leu³⁰-Asp⁷⁷LSTAADMQGVVlDGMASGLDKDYLKPDD (SEQ ID NO. 13), p18b Val⁶⁰-Asp⁷⁷SGLDKDYLKPDD (SEQ ID NO: 3526), MAP, Mastoparan-7, and poly arginine(Arg-8, RRRRRRRR, SEQ ID NO: 3527) were synthesized by C S Bio, Inc.(Melo Park, Calif.). Peptides were received as lyophilized powderaliquoted and stored at −20° C. in air-tight desiccators. Ail peptideswere subsequently analyzed by mass spectrometry and reverse phase HPLCas 95% purity and mass balance.

Predictive Modeling for Azurin Peptides:

GENETYX software (ver. 6.1) was used to generate Robson structure modelsfor azurin derived peptides. Gamier, J., Osguthorpe, D. J., and Robson.B., J Mol Biol, 120: 97-120 (1978). The MAPAS Software was used topredict a given protein structure for strong membrane contacts anddefine regions of the protein surface that most likely form suchcontacts. Sharikov, Y. et al, Nat Methods. 5: 119 (2008). if a protein,i.e., azurin, has a membranephilic residue score (MRS) 3, membranephilicarea score (MAS) 60%, and coefficient of membranephilic asymmetry(K_(alpha))>2.5, there is a high probability that the protein has a truemembrane-con (acting region.

Peptide/Protein Labeling:

Peptides were dissolved in 1 ml PBS mixed with Alexafluor 568 dye(Molecular Probes, Eugene, Oreg.) at a 1:2 protein:dye ratio, 100 μlsodium bicarbonate added, and the mixture incubated overnight at 4° C.with continuous stirring. Labeled peptide was separated from free dye bydialyzing against cold-PBS using Slide-A-Lyzerg Dialysis Cassettes 1000MWCO for p1 2 (SEQ ID NO; 3506) and 2000 MWCO for others (PierceBiotechnology, Rockford, Ill.).

Cell Penetration Confocal Analysts:

Cells were seeded on glass coverslips and allowed to attach overnight at37° C. under 5% CO₂. Cells were rinsed with fresh media and incubated at37° C. for 2 hrs in pre-warmed media containing Alexafluor 568 labeledazurin peptides (20 μM) or Arg-8 (SEQ ID NO: 3527) (5 μM), or mediaalone. Following incubation, coverslips were rinsed 3× with PBS, cellsfixed in 2.5% formalin for 5 min, and washed 2× in PBS, once in d.i.H₂O, and coverslips mourned in media attaining 1.5 μg/ml DAPI fornuclear counter staining (VECTASHIELD® Vector Laboratories, BurlingameCalif.). Cellular uptake and distribution were photographed under an invetted confocal laser scanning microscope (‘Model LC510, Carl Zeissinc., Gottingen, Germany).

Peptide co-localization with lysosomes or mitochondria was determined byincubating cells growing on a glass coverslip for 2 hrs at 37° withAlexafluor 568 labeled azurin or peptides. Mitrotracker (MitroTracker®Green FM Invitrogen Corporation, Carlsbad, Calif.) or lysotracker(LysoTracker® Green DND-26 Invitrogen Corporation, Carlsbad, Calif.) wasadded (final concentration 1 μM) for the last 30 mins of incubation.Cells were rinsed 3× with PBS, fixed in 2.5% formalin for 5 mins, washed2× with PBS and incubated in 0.1% Triton-X 100 in PBS for 15 min. Cellswere then incubated with 1 μg/ml rabbit anti-human golgin 97 oranti-human caveolin I (Abeam, Cambridge, Mass.) in PBS with 1% BSA.After 1 hr incubation at 4° C., coverslips were washed once with PBS,incubated 10 min in PBS containing Alexafluor 468 conjugated goatanti-rabbit antibody, washed 2× in PBS and once in d.i.H20. Coverslipswere then mounted in media containing 1.5 μg/ml DAPI for nuclear counterstaining. Colocalization (yellow) of Alexafluor 568 (red) and Alexafluor468 (green) was analyzed and photographed.

UISO-Mel-2 cells on coverslips were preincubated in MEM-E containing 100μg/ml heparin sulfate (Sigma-Aldrich, St. Louis, Mo.) for 30 min and p18(SEQ ID NO: 14), p28 (SEQ ID NO; 13) or Arg-8 (SEQ ID NO: 3527) added tobring the final concentration to 20 μM. After 1 hr, coverslips werewashed, fixed, and analyzed as described above.

Cell Penetration by FFACS:

Cells (1.0×10⁶/500 μl PBS) were incubated for 2 hrs at 37° C. withAlexafluor 568 labeled p18 (SEQ ID NO: 14) or p28 (SEQ ID NO: 13) (20μM), Arg-8 (SEQ ID NO: 3527) (5 μM), or media alone, washed 3× in PBS,fixed in 2.5% formalin for 5 min, washed twice in PBS, resuspended in200 μl PBS, and passed through a screen to obtain a single cellsuspension. Samples were analyzed with a MoFlo Cell Sorter (Dako,Glostrup, Denmark) λ_(ex) 508 nm and λ_(em) 603 nm and the fold increaseof the mean fluorescence intensity over background levels calculated.Results represent mean fluorescence of three separate experiments.

Entry Inhibitors:

UISO-Mel-2 cells (3×10⁵ per 300 μl), maintained in phenol red-,serum-free MEM-E at 37° C., were pretreated with inhibitors, including;Chloropromazine (inhibitor of clathrin-mediated endocytosis, 10 ml, 60min); Amiloride (macropinocytosis inhibitor, 50 μM, 30 min); Nystatin(50 μg/ml, 30 min); Methyl-β-cyclodextrin (MβCD, 5 mM, 60 min); Filipin(inhibitor of caveolae-mediated endocytosis, 3 μg/ml, 60 min); Taxol(microtubule stabilizer, 20 μM, 30 min); Staurosporine (cell cycleinhibitor, 250 nM, 10 min); Sodium azide (metabolic inhibitor, 1 mM, 60min); Oauabain (ATPase-dependent Na+/K+ pump inhibitor, 50 mM, 60 min);Brefeldin A (BFA; Golgi apparatus disrupter, 100 μM, 60 min); Wortmannin(early endosome inhibitor, 100 nM, 30 min); Monensin (inhibits at lateendosome/lysosome, 10 μM, 60 min); Nocodazole (inhibits caveosomeformation, 10 mM, 60 min); Cytochalasin D (actin filament andmicrotubule disrupter, 5 μM, 30 min); Benzyl2-acetamido-2-deoxy-α-D-galactopyranoside (BnGalNac; O-linkedglycosylation inhibitor, 3 mM, 48 hrs); Tunicamycin (N-linkedglycosylation inhibitor, 20 μg/ml, 48 hrs); and Neuraminidase (cleavesialic acid residues from proteins, IU/ml, 30 min). Final concentrationswere derived from the dose response curves of individual inhibitors.Alexafluor 568 labeled p18 (SEQ ID NO: 14) or p28 (SEQ ID NO: 13) (20μM) were then added, incubated for 1 hr, and the cells washed, fixed andprepared for flow cytometric analysis as described above.

Cell Membrane Toxicity Assays/LDH Leakage Assay:

An LDH leakage assay was performed according to the manufacturer'sinstructions (CytoTox-One, Promega, Wis.) with 100 μl of UISO-Mel-2cells (5×10³). Cells without peptides/proteins were used as a negativecontrol. Experiments were carried out in triplicate (data representmean±SEM).

Hemolysis Assay:

Human whole blood samples (2-3 ml) were centrifuged for 10 min at1000×g, and the pellets washed once with PBS and once with HKR bufferpH7.4 (18). Cell pellets were then resuspended in HKR buffer to 4%erythrocytes, 50 μl transferred to a 1.5 ml tube with 950 μl ofpeptides, azurin (5, 50 and 100 μM) or 0.1% Triton X-100 in HRK bufferto completely disrupt the RBC membrane. MAP and Mastoparan (BachemCalifornia, Inc., Torrance, Calif.) were used as positive controls.After 30 min incubation at 37° C. with rotation, tubes were centrifugedfor 2 min at 1000×g, 300 μl of supernatants transferred to a 96-wellplate and absorbance recorded at 540 nm.

Kinetics of Entry:

UISO-Mel-2 cells (5×10⁵ cells) in 1.5 ml lubes were suspended in MEMEmedia without phenol red. Reactions were started by adding either Alexafluor 568-conjugated p18 at 0, 10, 20, 50, 100, 150 and 200 μM for 5,10, 15 and 20 sec., or Alexafluor 568-conjugated p28 (SEQ ID NO: 13) at1, 10, 25, 50, 100, 150 and 200 μM for 30, 60, 90 and 120 sec on ice.After incubation, 1 ml of cold-PBS was added to the 250 μl reaction inmixture. Cells were centrifuged twice at 600×g for 2 min at 4° C. Atleast 10,000 fixed cells were analyzed by flow cytometry in eachreaction and their background and relative fluorescence calculated.

I¹²⁵ Labeling of Azurin and Competition Assays:

Peptide binding and entry was determined using a whole cell assay withUISO-Mel-2 cells in HERBS solution (50,000 cells/ml), were incubated for30 min at 37° C. with increasing concentrations (Q-175 nM) ofradiolabeled azurin in the presence/absence of 1000 fold excess ofunlabeled p18 (SEQ ID NO: 14), p28 (SEQ ID NO: 13), or azurin, thenwashed 3 Times with ice cold PBS, and radioactively remaining in thecell pellet counted using a gamma counter. Radioactivity in cellsincubated with I¹²⁵ azurin alone was considered total binding;radioactivity in the presence of unlabeled azurin, p18 (SEQ m NO: 14),or p28 (SEQ ID NO: 13) was considered nonspecific binding. Specificbinding was determined by subtracting nonspecific binding from totalbinding and Scatchard plots generated.

Example 3—N-Terminal Domain of p28 (SEQ ID NO: 13) Responsible forPreferential Entry into Cancer Cells

Initial data from peptide-GST constructs defined amino acids 50-77 ofazurin as a putative PTD for cell penetration, which fits well withstructural evidence for an α-helical region encompassing residues 54-67of azurin stabilizing the azurin molecule. Confocal analyses initiallysuggested that p28 (SEQ ID NO: 13) and p18 (SEQ ID NO: 14) of p28/azurin(FIG. 6A) penetrated human melanoma, prostate, lung, breast and ovariancancer cells with relatively similar efficiency, but did not penetratehistologically matched normal cell lines to the same degree (FIGS. 6Aand 6B). A singular exception was CCD13-Lu, a cell line derived fromlung fibroblasts. The cationic Arg-8 (SEQ ID NO: 3527) was rapidly andefficiently taken up into fibroblasts (FIGS. 6A and 6B) and all othernormal cell lines tested (data not shown).

These observations were essentially confirmed by a more sensitive FACsanalyses (FIG. 6C) where p28 (SEQ ID NO: 13) fluorescence was about0.5-6 and p18 (SEQ ID NO: 14) about 0.5-3 fold higher than thecorresponding normal cell line, with the exception of lung cancer. Asimilar pattern in intracellular fluorescence intensity was observedwithin a histopathologic subtype, melanoma, where the relative intensityof p18 (SEQ ID NO: 14) was about 50% of that observed with p28 (SEQ IDNO: 13) (FIG. 6D). Fluorescence intensity over background was alsoconsistently lower in normal and cancer cell pairs exposed to p18 (SEQID NO: 14) han p28 (SEQ ID NO: 13) (data not shown), again suggestingless p18 entered individual cells. In all cases, the degree of entry ofp18 (SEQ ID NO: 14) and p28 (SEQ ID NO: 13) into either cancer or normalcells was significantly less than that observed with Arg-8 (SEQ ID NO:3527), where no preference for entry was observed (FIGS. 6A and 6B). Thepredicted Robson structure (data not shown) of p18 (SEQ ID NO: 14)suggests that the C-terminal amino acids form a partial β-sheet. Thisand the shorter length of p18 (SEQ ID NO: 14), which lacks thehydrophilic C-terminal 10 amino acids (amino acids 68-77) of p28 (SEQ IDNO: 13), suggests that p18 (SEQ ID NO: 14), as a putative PTD forazurin, may have a more rapid entry into cancer and normal cells via anon-endocytotic over an endocytotic or membrane receptor mediatedprocess. MAPAS data (MRS 3.74, MAS 87.1, K_(mpha) 2.37) predict thatamino acids 69, 70, 75, 76, 85 of azurin provide the best opportunityfor membrane contact, suggesting the C-terminal region of p28 (SEQ IDNO: 13), not present on p18 (SEQ ID NO: 14) (amino acids 50-67) is mostlikely to contact specific residues on the cell membrane, irrespectiveof a cell's status.

The preferential penetration of p18 (SEQ ID NO: 14) and p28 (SEQ ID NO:13) was confirmed by exposing the same cell lines to azurin 60-77(p18b), or amino acids 66-77 (p 12), the C-terminal 12 amino acids ofp28 (SEQ ID NO: 13) (FIG. 7A, B). Here, the preferential penetrationobserved with p18 (SEQ ID NO; 14) and p28 (SEQ ID NO: 13) was completelyabolished. p18b (SEQ ID NO: 3526) (theoretical pI 4.13) has a shorta-helix and partial 13-sheet, and is extremely hydrophilic whichtogether may negate preferential entry, p12 (SEQ ID NO: 3506)(theoretical pI 4.33) lacks a secondary α-helical structure, but is alsohydrophilic suggesting overall hydrophilicity may be a major contributorto the decrease m selectivity of cell penetration.

Example 4—Cell Penetration is not a Result of Membrane Disruption

Cell penetration by azurin, p28 (SEQ ID NO: 13), and p18 (SEQ ID NO: 14)does not result from membrane disruption. An LDH leakage assay usingUISO-Mel-2 cells in the presence of 5-100 μM p28 (SEQ ID NO: 13), p18(SEQ ID NO: 14) or azurin (FIG. 8A) suggested that neither peptide norazurin entered cells by altering plasma membrane integrity (18). Thelack of membrane disruption was confirmed by determining the hemolyticactivity of azurin, p28 (SEQ ID NO: 13), and p18 (SEQ ID NO: 14) onhuman erythrocytes against the receptor mimetic MAP and mast celldegranulating peptide mastoparan 7, which translocates cell membranes asan amphipathic alpha-helix, and activates heterotrimeric G proteins.Mastoparan 7 caused complete cell lysis at 25 μM, while azurin, p28 (SEQID NO: 13), and p18 (SEQ ID NO: 14) had no hemolytic effect whencompared to control (no peptide) (FIG. 8B).

Example 5—p18/p28 Penetration is Energy Dependent and Saturable

The penetration of p28 (SEQ ID NO: 13) (FIG. 9A) and p18 (SEQ ID NO: 14)(FIG. 9B) into UISO-Mel-2 cells is temperature dependent. Cellpenetration and intracellular transport occurs relatively slowly over 3hr at 4° C., while entry and intracellular transport through variouscompartments is rapid at 22 and 37° C. as p18 (SEQ ID NO: 14) and p28(SEQ ID NO: 13) were present in the nucleus of UISO-Mel-2 cells within 2hrs post exposure. The penetration of 5 μM p28 (SEQ ID NO; 13) (FIG. 9C)or p18 (SEQ ID NO: 14) (FIG. 9D) into UISO-Mel-2 cells after 30 min inthe presence of a 200 fold excess of unlabeled peptide was severelycurtailed, suggesting that entry was a saturable process and specificreceptors or cell surface proteins or specific residues were, at leastin part, responsible for initial entry.

Example 6—Kinetics of p28 (SEQ ID NO; 13) and p18 (SEQ ID NO: 14)

The kinetics of p28 (SEQ ID NO: 13) and p18 (SEQ ID NO: 14) entry intoUISO-Mel-2 cells relative to human fibroblasts was calculated afterincubation, when cells were fixed and mean fluorescence intensity (MFI)determined. The Km and Vmax of each peptide were calculated by plottingpeptide concentration (μM) vs. velocity (MFI/sec) or by Scatchardanalysis. Although the penetration of azurin fragments 50-67 (p18: Vmax2.46, Km 101.6) and 50-77 (p28: Vmax 1.87, Km 159.1) into cancer andnormal cells (Vmax 2.88, Km 102.1 and Vmax 1.89, Km 166.0, respectively)differs significantly from each other, with p18 (SEQ ID NO: 14) entering−42% faster, the rate of the entry of each peptide into normal andcancer cells is virtually identical. The increase in amount offluorescence following exposure of cancer cells to p28 (SEQ ID NO: 13)relative to p18 is likely due to the increase in the amount of p28 (SEQID NO: 13) entering malignant cells. ¹²⁵I azurin and p18 (SEQ ID NO: 14)bound to UISO-Mel-2 cells with a similar affinity. In contrast,significantly more p28 (SEQ ID NO: 13) (K_(d) 2.5 μm, Bmax 3.0 pm) boundto UISO-Mel-2 cells with a higher affinity when exposed for a longerperiod of time (20 min vs. 2 min) at a higher temperature (37° C. vs. 4°C.) than either p18 (SEQ ID NO: 14) (K_(d) 18 min, Bmax 0.51 pm) orazurin (K_(d) 10 nm and 0.48 pm). These results suggest that azurin, p28(SEQ ID NO: 13), and p18 (SEQ ID NO: 14) all bind with relatively highaffinity and capacity to a site on the cancer and normal cell surfaceprior to entry, but may enter via more than one mechanism.

Example 7—p18/p28 Penetration Involves Caveolae and the Golgi Complex

As a class, cationic CPPs such as pTat and Arg-8 (SEQ ID NO: 3527) entercells by initially binding to anionic, sulfated proteoglycans prior toendocytosis. Incubation of p28 (SEQ ID NO: 13) and p18 (SEQ ID NO: 14)and Arg-8 (SEQ ID NO: 3527) with UISO-Mel-2 cells under serum freeconditions in the presence/absence of 100 μg/ml heparin sulfite (HS)significantly reduced the amount of intracellular Arg-8 (SEQ ID NO:3527), but did not alter the entry of either p28 (SEQ ID NO: 13) or p18(SEQ ID NO: 14) (FIG. 10A). The penetration of p18 (SEQ ID NO: 14) andp28 (SEQ ID NO; 13) into UISO-Mel-2 cells in the presence or absence ofa specific inhibitor of O-linked glycosylation, BnGalNac, andneroaminidase, which cleaves sialic acid residues, was furthercharacterized (FIG. 10B), and no inhibition of penetration was observed.However, tunicamycin, an inhibitor of N-linked glycosylation,significantly reduced the penetration of p18 (SEQ ID NO: 14) and p28(SEQ ID NO: 13) across the cell membrane.

The entry of p18 (SEQ ID NO: 14) and p28 (SEQ ID NO: 13) into UISO-Mel-2cells was also analyzed using inhibitors of energy dependent transportmechanisms, i.e., ATP. Sodium azide (FIG. 10B) and ouabain (Na⁺K⁺ ATPasepump) did not significantly inhibit the penetration of either peptidesuggesting non endocytotic pathways might also be involved in thepenetration of these peptides. Chlorpromazine CPZ), a specific inhibitorof clathrin mediated endocytosis, also had no effect on penetration, nordid the macropinocytosis inhibitor amiloride. (FIG. 10B). Stabilizationof microtubules with taxol had no effect on penetration, but disruptionof actin filaments and macropinocytosis with Cytochalasin D produced asmall (−20%), reproducible inhibition of the penetration of p18 (SEQ IDNO: 14) and p28 (SEQ ID NO: 13). The lack of effect of amiloridesuggests that the inhibitory activity of Cytochalasin D is probablythrough its effect on actin filaments.

Inhibition of the cell cycle with staurosporine did not blockpenetration, suggesting that penetration was not cell cycle specific.The lack of effect of staurosporine on p18 (SEQ ID NO: 14) and p28 (SEQID NO: 13) penetration of the cancer cell plasma membrane also suggeststhat a Src kinase/tyrosine kinase dependent pathway was not involved inpenetration, was dynamin independent, and hence independent of caveolaebudding. Neither p18 (SEQ ID NO: 14) nor p28 (SEQ ID NO: 13)co-localized with flotillin-1 (data not shown) a protein that resideswithin the plasma membrane and in a specific population of endocyticintermediates, again arguing against a role for flotillin and dynamin ininternalization. In contrast, nocodazole, which disrupts caveolaetransport and inhibitors of cholesterol mobilization and hence,caveolae-mediated endocytosis, inhibited penetration 50-65%.

The intracellular disposition of p18 (SEQ ID NO: 14) and p28 (SEQ ID NO:13) was then analyzed using wortmannin, an inhibitor of early endosomeformation, monensin, which inhibits late endosome/lysosome, andbrefeldin A (BFA), a disrupter of the Golgi apparatus. Wortmannin didnot block the intracellular accumulation of either p18 (SEQ ID NO: 14)or p28 (SEQ ID NO: 13) suggesting that, unlike cholera toxin, a caveolaeto early endosome pathway is not involved in the intracellulartrafficking of p18 (SEQ ID NO: 14) and p28 (SEQ ID NO: 13). The lack ofearly endosome involvement in the intracellular trafficking of p18 (SEQID NO: 14) and p28 (SEQ ID NO: 13) also suggests that clathrin mediatedendocytosis is not involved in internalization of these peptides.

However, monensin (Figure JOB) and BFA reduced the intracellularaccumulation of both peptides with a greater inhibitory effect on p28(SEQ ID NO: 13) (˜30%) than p18 (SEQ ID NO: 14) (˜10%) (FIG. 10B). Thepenetration of p28 (SEQ ID NO: 13) and p18 (SEQ ID NO: 14) intofibroblasts was also inhibited by MβCD, nocodazole, monensin andtunicamycin, but not by amiloride, sodium azide, and CPZ (FIG. 10C).This suggests that at least one mechanism of entry into cancer andnormal cells may be similar, but additional preferential accumulationinto cancer cells may be a function of the number of common membranereceptors or structures, i.e., caveolae (FIG. 10D, panels 1, 2).Alexafluor 568 labeled p18 (SEQ ID NO: 14) and p28 (SEQ ID NO: 13)co-localized with caveolin-1 and golgin 97 antibodies (FIG. 10D panels1,2). This confirms that these organelles are involved in theintracellular trafficking of p18 (SEQ ID NO: 14) and p28 (SEQ ID NO:13). Interestingly, azurin, but neither p18 (SEQ ID NO: 14) nor p28 (SEQID NO: 13) colocalized with mitochondrial specific fluorescence (FIG.10D panel 3). In contrast, p28 (SEQ ID NO: 13) and azurin, but not p18(SEQ ID NO: 14), co-localized with lysosomes (FIG. 10D panel 4).

Example 8—Functional Analysis of p28 (SEQ ID NO: 13) and p18 (SEQ ID NO:14)

Azurin inhibits the growth of several human cancer cell lines in vitroand in vivo. FIGS. 11 A and B illustrate the effect of p18 (SEQ ID NO:14) and p28 (SEQ ID NO: 13) relative to azurin and dacarbazine (DTIC) onUISO-Mel-2 cells as determined by MTT and cell count. After 72 hrsexposure, azurin decreased (p<0.05) cell survival at 100 and 200 μM-15%(FIG. 11A). p28 (SEQ ID NO: 13) had inhibited cell survival 14 and 22%(p<0.05) at 100 and 200 μM, respectively. In contrast, p18 (SEQ ID NO:14) had no effect, while dacarbazine (DTIC) produced a significantdose-related decrease on UISO-Mel-2 survival. Azurin and p28 (SEQ ID NO:13) (200 μM) also significantly decreased the survival of UISO-Mel-23and 29 cells. p18(SEQ ID NO: 14) had no effect on UISO-Mel-2 cellproliferation. The apparent increase (˜30-35%; UISO-Mel-2) in p28 (SEQID NO: 13) and azurin inhibition of melanoma cell proliferation, asmeasured by direct cell counting, suggests that the inhibitory effectmay reside primarily at the level of cell cycle with apoptosissubsequent to any delay. Although p18 (SEQ ID NO: 14) penetrated cancercells preferentially, unlike p28 (SEQ ID NO: 13), it had virtually noinhibitory activity on cell proliferation. This result demonstrates thatthe cytostatic and cytotoxic activity of p28 (SEQ ID NO: 13) lies in theC-terminal 10-12 amino acids of the sequence.

Example 9—Imaging p18 (SEQ ID NO: 14) and p28 (SEQ ID NO: 13) Entry intoMouse Organs

Small animal in vivo imaging has important significance in biologicalstudies, including human cancer research. The ability to track andvisualize a tagged biological probe allows researchers to visualizebiological processes and deduce mechanisms of action and efficacy.Imaging can be used to directly visualize trafficking of near infraredlabeled peptides of the cupredoxin class of proteins, including azurinand the azurin fragments p28 (SEQ ID NO: 13) and p18 (SEQ ID NO: 14), toprimary and metastatic tumor sites in xenograft bearing nude mice. JBiomed Optics 10:054010-1-11, 2005; J Amer Soc Exp Neuother 2:215-225,2005; Topics Curr Chem 222:1-29, 2002.

Procedure.

Athymic nude mice bearing Mel2 xenograft tumors were monitored untiltumor size reached 0-5 cm³. Mice were anesthetized using a mixture of2:1 ketamine:xylazine; recommended dosage is 10 μl/gm mouse b.w. s.c.Anesthetized mice were scanned directly before and after injection oflabeled peptide with an iCor Odyssey Imager. Anesthetized mice wereinjected i.v. (tail vein) with 100 μl of IRDye™ 800cw labeled p18/p28 ata concentration of 1.23 μg/μl-125 μg per mouse. Mice were scanned atleast once every 24 hours until excess dye cleared their system(generally-5 days). On the fifth day, mice were sacrificed andindividual animals scanned a final time. Organs, including the kidneys,stomach, intestine, spleen, brain, heart, and lungs, and tumors wereexcised, split in half, and half were fixed for histologicalexamination. The other half of the organs and tumors was covered with asmall amount of PBS, and then scanned.

1. A peptide comprising: SEQ ID NO: 14 that has one or more modifiedresidues. 2-3. (canceled)
 4. The peptide of claim 1 wherein the one ormore modified residues includes more than one residue that has beencyclized.
 5. The peptide of claim 4 wherein the residues are cyclized byenzymatic cyclization.
 6. The peptide of claim 4 wherein the cyclizedresidues comprise a thioether.
 7. The peptide of claim 4 wherein thecyclized residues comprise a lactam bridge.
 8. The peptide of claim 6wherein the thioether is formed by the addition of cysteine residues todehydroalanine and dehydrobutrine residues.
 9. The peptide of claim 8wherein said dehydroalanine and dehydrobutrine residues originate fromdehydration of serine and threonine respectively. 10-16. (canceled) 17.The peptide of claim 1, the one or more modified residues comprises oneor more asparagine or serine residues in the peptide is replaced with anamino acid residue other than asparagine or serine.
 18. The peptide ofclaim 17, wherein the asparagine or serine residue is replaced withglutamic acid or threonine residues.
 19. (canceled)
 20. The peptide ofclaim 1, wherein the one or more modified residues comprises one or moreglycine residues of the peptide that are replaced with an amino acidresidue other than glycine.
 21. The peptide of claim 20, wherein one ormore glycine residues are replaced with a threonine or alanine residue.22-23. (canceled)
 24. The peptide of claim 1, wherein the one or moremodified residues comprises one or more methionine or cysteine residuesof the peptide are replaced with another amino acid residue. 25.(canceled)
 26. The peptide of claim 1, wherein the one or more modifiedresidues comprises a glycine residue in positions 1, 2 or 3 from theN-terminus of the peptide replaced with an amino acid residue other thanglycine.
 27. The peptide of claim 1, wherein the one or more modifiedresidues comprises a proline residue in position 3 from the N-terminusof the peptide replaced with an amino acid residue other than proline.28. The peptide of claim 1, wherein the one or more modified residuescomprises an asparagine residue at the N-terminus of the peptidereplaced with an amino acid residue other than asparagine. 29.(canceled)
 30. The peptide of claim 1, wherein the one or more modifiedresidues comprises one or more amino acid residues of the peptidereplaced with the D-isomer of the amino acid residue.
 31. The peptide ofclaim 30, wherein each of the amino acid residues of the peptide isreplaced with the D-isomers of the amino acid residues.
 32. The peptideof claim 1, wherein the peptide comprises SEQ ID NO:
 45. 33. (canceled)34. The peptide of claim 1 wherein the one or more modified residuescomprises acetylation of the N-terminus of the peptide.
 35. The peptideof claim 1, wherein the one or more modified residues comprisesamidation of the C-terminus of the peptide.
 36. The peptide of claim 1,wherein the one or more modified residues increases the stability of itstertiary structure.
 37. The peptide of claim 36, wherein the one or moremodified residues increases the stability of a least one α-helix. 38.The peptide of claim 36 wherein the one or more modified residuescomprises a lactam bridge.
 39. The peptide of claim 36 wherein the oneor more modified residues comprises a unnatural amino acid.
 40. Thepeptide of claim 36 wherein the one or more modified residues comprisesan α-amino-isobutyric acid
 41. The peptide of claim 1, wherein at leastone amino acid residue of the peptide selected from the group consistingof glycine, proline, serine, aspartic acid, alanine, threonine, valine,glutamine, asparagine, cysteine, histidine, lysine, and arginine isreplaced with an amino acid residue selected from the group consistingof leucine, isoleucine, phenylalanine, glutamic acid, tyrosine,tryptophan, methionine and .alpha.-amino-isobutyric acid.
 42. Thepeptide of claim 1 comprising an amino acid sequence selected from thegroup consisting of SEQ ID NOS: 34-44.
 43. The peptide of claim 1,wherein two or more lysine residues of the peptide is substituted withε-(3,5-dinitrobenzoyl)-lysine residues in an i(i+4) spacing. 44.(canceled)
 45. The peptide of claim 1, wherein the one or more modifiedresidues comprises one or more pairs of native amino acid residues inthe peptide substituted with α,α-disubstituted unnatural amino acidswith olefin-bearing tethers that correspond to the native amino acids.46. (canceled)
 47. The peptide of claim 1, wherein the one or moremodified residues comprises residues fused to Pep42 (SEQ ID. NO: 3505)via a cathepsin B-cleavable linkage.
 48. The peptide of claim 1, whereinthe one or more modified residues comprises an optically active aminoacid.
 49. A pharmaceutical composition, comprising the isolated peptideof claim 1 and a pharmaceutically acceptable carrier. 50-59. (canceled)60. The peptide of claim 1, which is conjugated with a nanoparticle. 61.The peptide of claim 60, wherein the nanoparticle is a noble metal. 62.The peptide of claim 61, wherein the noble metal is gold.
 63. Thepeptide of claim 60, which is conjugated with the nanoparticle via anelectron transfer path.